CZ20024149A3 - Pharmaceutical preparation - Google Patents

Abstract

The present invention provides pharmaceutical compositions for the treatment of a hepatitis C infection in a host, comprising an antivirally effective amount of a 2'-C-branched nucleoside or a 2'-C-branched ribofuranosyl nucleoside, or pharmaceutically acceptable salts or esters thereof, in combination with one or more other anti-HCV agent. The present invention further provides the use of a 2'-C-branched nucleoside or a 2'-C-branched ribofuranosyl nucleoside, or pharmaceutically acceptable salts or esters thereof, in the manufacture of a medicament for the treatment of a hepatitis C infection in a host.

Description

The invention also relates to a pharmaceutical composition for the treatment of hepatitis C. The invention also relates to certain novel active substances and their use for the manufacture of said pharmaceutical composition.

BACKGROUND OF THE INVENTION

Hepatitis C virus, HCV, is a major cause of chronic liver disease worldwide (Boyer, N. et al., J. Hepatol. 32: 98-112, 2000). HCV causes a slowly worsening viral infection and is a major cause of cirrhosis and hepatocellular carcinoma according to Di Besceglie, AM and Bacon BR, Scientific American, October, 80-85, 1999, Boyer, N. et al., J. Hepatol, 32: 98 Probably up to 170 million people in the world are infected with HCV according to Boyer N. et al., J. Hepatol. 32, 98-112, 2000. Cirrhosis, caused by chronic hepatitis C infection, causes 8,000 to 12,000 deaths per year in the United States alone, and HCV infection is also the leading cause of liver transplantation.

HCV is also the cause of at least 80% of hepatitis after transfusions and also constitutes a substantial proportion of sporadic acute hepatitis, HCV infection is also believed to cause a number of cases of so-called "idiopathic chronic hepatitis," cryptogenic cirrhosis and possibly hepatocellular carcinomas not associated with other hepatitis viruses such as hepatitis B virus, HBV. A small number of healthy people is also possible

2, and include it as a chronic HCV carrier in different geographical areas. The number of these carriers is probably significantly higher than the number of HBV carriers, although the information is preliminary. It is unclear how many of these people have subclinical chronic liver disease according to The Merck Manual, Chap. 69, p. 901, 16th edition, 1992.

HCV is classified as a member of the Fraviviridae family of viruses, including the genera flaviviruses, pestiviruses and hapaceiviruses, which include hepatitis C viruses according to Rice, C.M., Flaviviridae: The viruses and their replication. Fields Virology, eds. N., Knipe, D.,., And Howley, Ρ. Lippincott-Raven

Publishers, Philadelphia, PA, Chap. 30, 931-959, 1996. HCV is a virus that has an envelope containing positive single-stranded RNA of about 9.4 kb in the genome. The genome of the virus consists of a 5'-untranslated UTR, a long open reading frame that encodes a polyprotein precursor containing approximately 3011 amino acid residues and a short 3 'UTR. The 5 'UTR is the most conserved part of the HCV genome and is important for initiating and directing translation of the polyprotein. Translation of the HCV genome is initiated by a mechanism known as the intrinsic ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence referred to as the ribosome internal entry site, IRES. Recently one of the RNA structures has been shown to be an essential structural element of IRES HCV. Viral structural proteins include the nucleocapsid core protein (C) and two envelope glycoproteins, E1 and E2. HCV also contains the coding sequence for the two proteinases, a zinc-dependent metalloproeinase encoding the NS2-NS3 coding region and a serine protease encoding the NS3 coding region. These proteinases are necessary for cleavage of specific proteins

3 regions in the precursor polyprotein to form complete peptides. The carboxyl half of the non-structural protein 5, NS5B, contains RNA-dependent RNA polymerase. The function of the remaining non-structural proteins, NS4A and NS4B, and the function of NS5A (the amino-terminal half of the non-structural protein 5), remain unclear.

The efforts of researchers are currently focused on the development of means for treating chronic HCV infections in humans according to Di Besceglie, A.M. and Bacon, B. R., Scientific American, October, 80-85, 1999.

Currently, there are mainly two antiviral agents, ribavirin and interferon α, which can be used to treat chronic HCV infections in humans.

Treatment of HCV infection with ribavirin

Ribavirin, Ι-β-D-ribofuranosyl-11,2,4-triazole-3-carboxamide is a non-interferon inducing synthetic nucleoside analogue with a broad spectrum of activity and marketed under the trade name Virazole (The Merck Index, 11th ed., Ed. : Budavari, S., Merck et al., Inc., Rahway, NJ, p. 1304, 1989). US 3798209 and RE29835 disclose this substance as ribavirin. Ribavirin is structurally similar to guenosine and is active in vitro against several types of DNA and RNA viruses, including the Flaviviridae family of Gary L. Davis, Gastroenterology 118, S104-S114, 2000.

Ribavirin lowers serum aminotransferase concentrations to normal levels in 40% of patients, but does not lower blood serum HCV RNA levels according to Gary L. Davis, Gastroenterology 118, S104-S114, 2000. To • · ♦ «

means that ribavirin alone does not effectively reduce viral RNA concentration. In addition, ribavirin is relatively toxic and causes anemia.

Treatment of HCV infection with interferon

IFN interferons are substances that are used and commonly supplied for the treatment of chronic hepatitis in the last decade. These are glycoproteins produced by immune system cells in response to viral infection. Interferon induces replication inhibition in a number of viruses, including HCV, and when used as the sole agent for the treatment of hepatitis C infection, suppresses HCV RNA concentration to non-measurable levels. In addition, IFNs normalize blood serum aminotransferase concentrations. Unfortunately, all of these effects are temporary and lasting responses can only be achieved in 8 to 9% of patients with chronic HCV infection according to Gary L. Davis,

Gastroenterology 118, S104-S114, 2000.

A number of patent documents disclose treatment of HCV by the administration of Interferon. For example, US 5980884 (Blatt et al.) Describes methods for treating patients with HCV infection by interferons. US 5942223 (Bazer et al.) Describes the treatment of HCV using an interferon of a sheep or cattle. US 5928636 (Alber et al) discloses combination therapy with interleukin 12 and interferon and for infectious diseases including HCV. US 5908621 (Glue et al.) Describes the use of an interferon modified with polyethylene glycol for the treatment of HCV. 5849696 (Chretien et al) suggests the use of thymosins as such or in combination with interferon in the treatment of HCV infection. US 5830455 (Valtuena et al.) Discloses a combination of interferon and a free radical scavenger for the treatment of HCV. US 5738845 (Imakawa) discloses the use of human interferon tau in the treatment of HCV. Other methods of treating HCV using interferons are described in US 5676942 (Dough et al.),

US 5372808 (Blatt et al.) And US 5849696.

Combination of interferon and ribavirin

The combination of IFN and ribavirin in the treatment of HCV infection is reported to be effective in patients in whom IFN has not yet been used by Battaglia, A. M. et al., Ann. Pharmacother. 34: 487-494, 2000. The results are promising in people who have not yet developed hepatitis, as well as in people where histological disease has already been demonstrated by Berenguer M. et al., Antivir Ther. 3 (Suppl. 3):

125-136, 1998. The side effects that this treatment may accompany are hemolysis, symptoms, flu-like symptoms, anemia and fatigue according to Gary L. Davis,

Gastroenterology 118, S104-S114, 2000.

Further literature on the treatment of HCV infection

A number of treatments for HCV infection are reported in Bymock et al., Antiviral Chemistry and Chemotherapy, 11: 2, 79-95, 2000.

Several NS3 protease inhibitors have been identified in the literature where the amide bond in the cleaved substrate is replaced by an electrophilic bond, which then interacts with the catalytic serine as described in Attwood et al., 1998, Antiviral Peptide derivatives, 98/22496 , Attwood et al., 1999, Antiviral Chemistry and Chemotherapy 10.259-273, · »··

Attwood et al., 1999, Preparation and use of amino acid derivatives as anti-viral agents, DE 19914474, Tung et al., 1998, Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, WO 98/17679. Said inhibitors terminate with an electrophilic group, for example a boric acid residue or phosphonate, as disclosed in Llinas-Brunet et al., 1999, Hepatitis C inhibitor peptide analogues, WO 99/07734. Two classes of electrophilic group inhibitors, α-ketonamides and hydrazinurea, have been described.

A number of other non-substrate based inhibitors are also described in the literature. For example, the inhibitory effects of 2,4,6-trihydroxy-3-nitrobenzamide derivatives against HCV protease and other serine proteases were evaluated according to Sudo K. et al., 1997, Biochemical and Biophysical Research Communications, 238: 643-647, Sudo, K. et al., 1998, Antiviral Chemistry and Chemotherapy, 9: 186. Two most active compounds, RD3-4082 and RD3-4078, were identified using reverse phase HPLC, the first of which is substituted on the amide group by a chain of 14 carbon atoms, the second of these, it contains p-phenoxyphenyl groups.

Furthermore, thiazolidine derivatives have been identified as micromolar inhibitors using reverse phase HPLC together with the NS3 / 4A fusion protein and the NS5A / 5B substrate, according to Sudo, K. et al., 1996,

Antiviral Research 32: 9-18. RD-1-6250, which contains a fused long alkyl chain substituted cinnamic acid residue, was most effective against the isolated enzyme. Two other examples of active ingredients are RD4 6205 and RD4 6193.

Further literature discloses a relatively small pot using an ELISA, identifying 3 compounds as active inhibitors, one of which is thiazolidine and two are benzanilides according to Kakiuchi N. et al., J. EBS Letters 421: 217-220, Takeshita N. et al., Analytical Biochemistry 247: 242-246, 1997.

Several US patents disclose protease inhibitors for use in the treatment of HCV infection. E.g. US 6004933 (Spruce et al.) Discloses a class of cysteine protease inhibitors for inhibiting endopeptidase 2 HCV. US 5990276 (Zhang et al.) Discloses synthetic inhibitors of hepatitis C virus NS3 protease. The inhibitor consists of a subsequence of the NS3 protease substrate or the NS4A cofactor substrate. The use of restriction enzymes to treat HCV infection is described in US 5538865 (Reyes et al.).

The isolate from the fermentation broth of Streptomyces sp., Sch 68631, phenan-threnequinone has molecular activity against HCV protease in SDS-PAGE and in autoradiographic assays according to Chu M. et al. Tetrahedron Letters 37: 7229-7232, 1996. compound, Sch 351633, isolated from Penicillium griseofulvum, which has micromolar activity in the scintillation assay of Chu M. et al. Bioorganic and Medicinal Chemistry Letters 9: 1949-1952. Nanomolar activity against HCV NS3 protease was achieved by the construction of selective inhibitors based on the macromolar compound eglin c. This pore-isolated substance is a potent inhibitor of several serine proteases such as protease A and B of S. griseus, α-chymotrypsin, chymase and subtilisin according to Qasim MA et al., Biochemistry, 36: 1598-1607, 1997.

HCV hecase inhibitors have also been described in US 5633358 (Diana GD et al. And WO 97/36554 (Diana GD et al.). There are also several references to HCV polymerase inhibitors. These are some nucleotide analogues, gliotoxin and the natural product cerulenin according to publications. Ferrari R. et al., Journal of Virology, 73: 1649-1654, 1999; Lohmann V. et al., Virology 249: 108118, 1998.

Antisense phosphothiate oligodeoxynucleotides complementary to extended sequences in the 5'-non-coding region of HCV have been reported to be effective inhibitors of HCV gene expression in in vitro translation and in IlCV-luciferase-producing cell cultures of IlCV-luciferase according to Alt M. et al., Hepatology, 22: 707 -717, 1995. Recently, nucleotides 326-348, forming the 3'-end of the NCR, and nucleotides 371 to 388, deposited in the coding region of the HCV RNA core, have been shown to be effective target structures for inhibiting viral translation induced by Atl antisense structures. M. et al., Archives of Virology, 142: 589-599, 1997. US 6001990 (Wands et al.) Describes oligonucleotides that inhibit HCV replication. WO 99/29350 discloses compositions and methods for treating hepatitis C infection by administering antisense oligonucleotides that are complementary to and hybridizable to HCV RNA. US 5922857 (Han et al.) Discloses nucleic acids corresponding to the sequence of the pestivirus IV region to control the translation of HCV. Recently, antisense oligonucleotides have been reported to be useful for therapeutic purposes according to Galderisi U. et al., Journal of Cellular Physiology 181: 251-257, 1999.

IRES-dependent translation inhibitors are also disclosed, for example, in JP-08268890 (Ikeda N. et al.). JP-10101591 (Kai Y. et al.). Nuclease resistant ribozymes have been targeted by IRES and are reported to be inhibitors of the chimeric HCV poliovirus assay of Maccjak DJ et al., Hepatology 30 abstract 995, 1999. The use of ribozymes to treat HCV is also described in US 6043077 (Barber et al.) , US 5869253 and US 5610054 (both Draper and others).

Other patents disclose the use of immune-enhancing agents in the treatment of HCV. For example, US 5001799 (Chretien et al.) Proposes a method of treating hepatitis C in patients who do not respond to interferon treatment by administering thymosin or a fragment of thymosin as potentiators of immune system activity. US 5972347 (Eder et al.) And US 5969109 (Bona et al.) Describe the treatment of HCV based on antibodies.

US 6034134 (Gold et al.) Discloses certain compounds having an immunomodulatory, anti-malarial and anti-Borna virus and hepatitis C virus agonist activity at NMDA receptors. These substances belong to the group of 1-aminoalkylcyclohexanes. US 6030960 (Morris-Natschke et al.) Proposes the use of certain alkyl lipids to inhibit hepatitis-induced antigen production, including HCV-produced antigens. US 5922757 (Chojkier et al.) Describes the use of vitamin D and other antioxidants for the treatment of various liver disorders including HCV. US 5858389 (Elsherbi et al.) Proposes the use of squalene for the treatment of hepatitis C. US 5849800 (Smith et al.) Describes the use of amantadine for the treatment of hepatitis C. US 5846964 (Ozeki et al.) Proposes the use of bile acids for the treatment of HCV. According to US 5491135 (Blough et al.), N- (phosphonoacetyl) -L-aspartic acid can be used to treat flavivirus infections such as HCL.

Other compounds that are proposed for the treatment of HCV include plant estracts according to US 5837257 (Tsai et al), US 57258549 (Omer et al) and US 6056961, further piperidines according to US 5830905 (Diana et al), benzenedicarboxamides according to US 5633388 (Diana et al. others), polyadenylic acid derivatives according to US 5496546 (Wang et al.), 2 ', 3'-dideoxyinosine according to US 5026687 (Yarchoan et al.) and benzimidazoles according to US 5891874 (Colacino et al.).

Since hepatitis C infection has reached epidemic levels worldwide and has tragic consequences for infected patients, there remains a need to find new pharmaceutical compositions for treating the disease. Said compositions should have low toxicity.

SUMMARY OF THE INVENTION

The invention relates to pharmaceutical compositions for the treatment of hepatitis C infection. These compositions comprise an effective amount of β-D- or β-L-nucleosides of formulas I to XVIII or an effective amount of a pharmaceutically acceptable salt or precursor thereof.

In a first embodiment, the invention relates to compounds of formula I

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a .ί · • 12.

R ⁴ and R ^{5 are} independently hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts or prodrugs thereof.

In a second embodiment, the present invention provides a compound of formula II

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable cleavable moiety. group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a third embodiment, the present invention provides a compound of formula III

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group,

a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or be another pharmaceutically acceptable cleavable group to cleave in vivo to give a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a fourth embodiment, the present invention provides a compound of formula IV

(IV): &> · ·: 1 & where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

According to a fifth embodiment, the present invention provides a compound of formula V

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

17.

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a sixth embodiment, the present invention provides a compound of formula VI

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after cleavage in

18.

in vivo, a compound is formed wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

According to a seventh embodiment, the compounds of formula (VII), (VII) and (IX) are provided

Base

OR ² OR ³

(IX) wherein the base is a purine or pyrimidine base as defined,

R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di- or triphosphate and a stabilized phosphate precursor) .acvl including lower acyl, alkyl including lower alkyl,

a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or be another pharmaceutically acceptable cleavable group to cleave in vivo to give a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue,

R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (O) O (alkyl), -C (O) O (lower) alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₂ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and.

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to an eighth embodiment, the present invention provides compounds of formulas X, XI and XII

(X) (XI)

wherein the base is a purine or pyrimidine base as defined,

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl),

-C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl),

-O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N ( acyl) ₂ a

X is O, S, SO ₂ or CH ₂

23, or a pharmaceutically acceptable salt or precursor thereof.

According to a further embodiment of the invention, the present invention provides compounds of formulas XIII, XIV and XV

(XV) wherein the base is a purine or pyrimidine base as defined,

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ < -N (acyl) _2, and

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

In a tenth embodiment, the present invention provides a compound of formula XVI

wherein the base is a purine or pyrimidine base as defined,

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid , the amino acid, carbohydrate, peptide, cholesterol or other pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ or R ^{2 is} independently hydrogen or phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to an eleventh embodiment of the present invention, the present invention provides a compound of formula (VII)

• * «· · ·

♦ ί * (XVII) wherein the base is a purine or pyrimidine base as defined;

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or

»·

A iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) 2, -N (acyl) _2, and

R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, ΝΟχ, NH2, - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) 2;

R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ ;

or a pharmaceutically acceptable salt or precursor thereof.

In a twelfth embodiment, the present invention provides a compound of formula XVIII r'o

Base

R ^s

R ⁹ R ⁷ (xvm) wherein the base is a purine or pyrimidine base as defined,

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or trisphosphate and a stabilized phosphate precursor), an acyl including a lower acyl group, and a sulfonate ester group *

alkyl including lower alkyl including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, a residue an amino acid, carbohydrate, peptide, cholesterol, or other pharmaceutically acceptable leaving group, which, after cleavage in vivo, yields a compound wherein R ¹ or R ^{2 is} independently hydrogen or phosphate,

R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chloro, bromo or iodo, NO ₂ , NH ₂ ,

-NH (lower alkyl), di (lower alkylamino),

R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X represents O, S, SO ₂ or CH ₂ or their pharmaceutically acceptable salts or prodrugs.

The β-D- and β-L-nucleosides of the invention are capable of inducing HCV polymerase inhibition. These nucleosides can be subjected to in vitro assays for inhibition of HCV polymerase according to the methods described below. The activity spectrum for each compound can be determined using the assays described below.

One possibility of monitoring the effect of a compound by measuring the efficacy of the substance concentration that is necessary to reduce the number of plaques in vitro by 50%, ie a EC ₅₀ for that substance. In a preferred embodiment, the compounds have an EC ₅₀ value of less than 25, 15, 10, 5 or 1 μηιοί.

In another embodiment, the active compounds may be administered in combination or in combination with other anti-HCV agents. In such combination therapy, the active ingredient of two or more compounds is administered together, while in alternating treatment the compounds are administered alternately. The doses of the active ingredients will depend on the rate of absorption, inactivation and excretion and other known factors. It will be appreciated that the dosage employed will also depend on the severity of the disease being treated. It should also be noted that in individual patients, specific dosages and methods of administration over time should be adapted to the patient's needs.

The following are examples of antiviral agents that can be used in combination with the compounds of the invention:

• ·

Interferon and / or ribavirin (Battaglia, A.M. et al., Ann. Pharmacother. 34: 487-494, 2000), Berenguer, M. et al., Antivir. Ther. 3 (Suppl. 3): 125-136 (1998).

2. Substrate NS3 Protease Inhibitors of Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998, Attwood et al., Antiviral Chemistry and Chemotherapy 10.259-273, 1999, Attwood et al., Preparation and use of amino acid derivatives as antiviral agents, DE 19914474, Tung et al., Inhibitors of serine proteases, paricularly hepatitis C virus NS3 protease, PCT WO 98/17679 including α-ketoamides and hydrazinureas and inhibitors which terminate by an electrophilic group, for example the boric acid residue or phosphonate according to Llinas -Brunet et al., Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.

3. Subostate-independent inhibitors, for example the 2,4,6-trihydroxy-3-nitrobenzamide derivatives of Sudo K. et al., Biochemical and Biophysical Research Communications, 238: 643-647, 1997, Sudo, K. et al., Antiviral Chemistry and Chemotherapy, 9: 186, 1998, including RD3-4082 and RD3-4078, the first of which is a substituted 14-carbon amide, the other of which contains a p-phenoxyphenyl group.

4. Thiazolidine derivatives which can be shown to be inhibited by reverse phase HPLC with the NS3 / 4A fusion protein and NS5A / 5B substrate according to Sudo K. et al., Antiviral Research, 32: 9-18, 1996, the specific compound being RD- 1-6250 containing a cinnamic acid residue substituted with a long alkyl chain as well as RD4 6205 and RD4 6193.

5. Thiazolidines and benzanilides according to Kakiuchi N. et al., J. EBS Latters 421: 217-220, Takeshita N. et al., Analytical Biochemistry 247: 242246, 1997.

6. Phenanthrenchinone with anti-HCV protease activity in SDS-PAGE and autoradiography, isolated from Streptomyces sp. Sch 68631 according to CHu, M. et al., Tetrahedron Letters 37: 7229-7232, 1996 and Sch 351633, isolated from Penicillium griseofulvum, is effective in the scintillation assay of Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949 -1952.

7. Selective NS3 inhibitors based on the elgin c macromolecule isolated from the pore according to Qasim M. A. et al., Biochemistry 36: 1598-1607, 1997.

8. HCV Helicase Inhibitors of Diana G. D. et al. Compounds, compositions and methods for the treatment of hepatitis C, US 5633358, Diana G. D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT

WO 97/36554.

9. HCV polymerase inhibitors, for example nucleotide analogues, gliotoxin according to Ferrari R. et al., Journal of Virology 73: 1649-1654, 1999 and the natural product cerulenin according to Lohmann V. et al., Virology 249: 108-118, 1998.

• ·, 3φ

10. Antisense phosphothioate oligodeoxynucleotides S-ODN, complementary to the extension of the sequence in the 5'-non-coding region of the HCV NCR according to Alt M. et al., Hepatology 22: 707-717, 1995, or nucleotides 326-348, containing the 3'-end of NCR and nucleotides 371-388, deposited in the IICV RNA core coding region of Alt M. et al., Archives of Virology 142: 589-599, 1997,

Galderisi U. et al., Journal of Cellular Physiology 181: 251-257, 1999.

11. Inhibition of IRES-dependent translation according to Ikeda N. et al., Agent for the prevention and treatment of hepatitis C, JP-08268890, Kai Y. et al., Prevention and treatment of viral diseases, JP-10101591.

12. Nuclease-resistant ribozymes according to Maccjak,

D. J. et al., Hepatology 30, abstract 995, 1999, a

13. Various other substances, such as 1-aminoalkylcyclohexanes of US 6034134 (Gold et al.), Alkyl lipids of US 5922757 (Chojkier et al.), Squalene, amantadine, bile acids according to US 5846964 (Ozeki et al.), N- (phosphonoacetyl) acid. -L-aspartic according to US 5830905 (Diana et al.), Benzenedicarboxamides according to US 5633388 (Diana et al.), Polyadenylic acid derivatives according to US 5496546 (Wang et al.), 2 ', 3'-dideoxyinosine according to US 5026687 (Yarchoan et al.) and benzimidazoles of US 5891874 (Colacino et al.).

The invention will now be further illustrated by the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows by way of example the structure of some nucleosides of the invention and other known FIAU and Ribavirin nucleosides which are used in the text of the invention for comparison.

Figure 2 is a graph for the concentration of β-0-2'-CH ₃ -riboG given to six Cynomolgus monkeys in blood plasma over time from the time of administration.

Figures 3a and 3b are graphs for the concentration of β-ϋ-2'-CH ₃ -riboG in blood plasma following administration of Cynomolgus monkeys intravenously (3a) or orally (3b) over time from the time of administration.

Accordingly, the present invention provides novel substances which have antiviral activity or are metabolized to substances having such activity. The compounds may be administered in an effective amount to patients with hepatitis C infection. These include, in particular, β-D- or β-L-nucleosides as described above, and their pharmaceutically acceptable salts or precursors, usually administered in the form of a pharmaceutical composition in association with a acceptable carrier.

The invention therefore relates to the following embodiments:

(a) β-D- and β-L-nucleosides as described above and their pharmaceutically acceptable salts and precursors;

(b) β-D- and β-L-nucleosides and their pharmaceutically acceptable salts and precursors for use in the treatment or prophylaxis of HCV infection, particularly in individuals who have been diagnosed with or at risk of having an infection;

c) use of said nucleosides and their pharmaceutically acceptable salts and prodrugs for the manufacture of a pharmaceutical composition for the treatment of HCV infection,

d) pharmaceutical compositions comprising said nucleosides or pharmaceutically acceptable salts or precursors thereof together with a pharmaceutically acceptable carrier or diluent;

(e) β-D- and β-L-nucleosides as described above, substantially free of enantiomers or substantially isolated from other chemicals;

f) a method for producing β-D- and β-L-nucleosides as described in more detail below; and

(g) a method for producing β-D- and β-L-nucleosides substantially free of enantiomers or substantially isolated from other chemicals.

I. Active substances and their physiologically acceptable salts and precursors

In a first embodiment, the present invention provides a compound of formula (I)

where (I) ·· * · · · ♦ «·

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, cleavage in vivo yields a compound in which R, R or R independently represents a hydrogen atom or a phosphate residue,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a preferred embodiment, the invention relates to a compound of formula I wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ represents a hydrogen atom,

X ² represents a hydrogen atom or an amino group;

34:

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

In a second embodiment, the present invention provides a compound of formula II

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, cleavage in vivo gives a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, · · · · ·

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a preferred embodiment, the invention relates to a compound of formula II wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ represents a hydrogen atom,

X ² represents a hydrogen atom or an amino group;

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

In a third embodiment, the present invention provides a compound of formula III

(ΙΠ) where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a preferred embodiment, the invention relates to a compound of formula III wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ represents a hydrogen atom,

X ² represents a hydrogen atom or an amino group;

3?

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

where

phosphate (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, the phenyl group being optionally substituted with one or a plurality of substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ , R 1 ² or R ³ independently represent a hydrogen atom or a phosphate residue,

Y is hydrogen, bromine, chlorine, fluorine, iodine or

OR ⁴ , NR ⁴ R ⁵ or SR ⁴

3δ

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ^{5 are} independently hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts or prodrugs thereof.

In a preferred embodiment, the invention relates to a compound of formula IV wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ is hydrogen or methyl,

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

According to a fifth embodiment, the present invention provides a compound of formula V

• · · · · · · · · · · ·

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a preferred embodiment, the invention relates to a compound of formula V wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ is hydrogen or methyl,

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

In a sixth embodiment, the present invention provides a compound of formula VI

where

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol, or other pharmaceutically acceptable leaving group. cleavage in vivo gives a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue;

Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4,

X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a

R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof.

In a preferred embodiment, the invention relates to a compound of formula VI wherein:

R ^1, R ² and R ³ independently represent a hydrogen atom or a phosphate, preferably hydrogen,

X ¹ is hydrogen or methyl,

Y represents a hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy group, as well as pharmaceutically acceptable salts or precursors thereof.

In a seventh embodiment, the present invention provides compounds of formulas VII, VIII and IX

Base

OR ² OR ³ (MV)

(TO)

42:

wherein the base is a purine or pyrimidine base as defined,

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to a first preferred embodiment of the seventh main embodiment, the invention relates to a compound of formula VII, VIII or IX, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl,

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a second preferred embodiment of the seventh main embodiment, the invention relates to a compound of formula VII, VIII or IX, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ are hydrogen,

R ⁶ is alkyl,

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a third preferred embodiment of the seventh main embodiment, the invention relates to a compound of formula VII, VIII or IX, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl,

X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

According to an eighth embodiment, the present invention provides compounds of formulas X, XI and XII.

• «· ·

OR ² OR ³

(X)

wherein the base is a purine or pyrimidine base as defined,

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups , such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or may be another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) 2, -N (acyl) ₂ ,

45.

· · «• • · ·

R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) ), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to a first preferred embodiment of the eighth main embodiment, the invention relates to a compound of formula X,

XI or XII, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl and

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a second preferred embodiment of the seventh main embodiment, the invention relates to a compound of formula X,

XI or XII, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ are hydrogen,

R ⁶ is alkyl and

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a third preferred embodiment of the seventh main embodiment, the invention relates to a compound of formula X, XI or XII, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl and

X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

According to yet another preferred embodiment of the eighth main embodiment, the invention relates to a compound of formula XI

(XI) wherein the base is a purine or pyrimidine base as defined above, optionally substituted with an amino or cyclopropyl group (i.e., 2-amino, 2,6-diamino or cyclopropylguanosine) and R ¹ and R ² independently represent hydrogen , phosphate residue (including mono-, di- or triphosphate and stabilized 47.):::: · · · · · · · · · · · · · · · · · · A phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or a plurality of substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group, cleavage in vivo yields a compound wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue.

According to a further embodiment of the invention, the present invention provides compounds of formulas XIII, XIV and XV

OR ² OR ³ (0Π0

wherein the base is a purine or pyrimidine base as defined,

R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and «» · ·

•>

wv benzyl, wherein the phenyl group is optionally substituted by one or a plurality of substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ , R 1 ² or R ³ independently represent hydrogen or a phosphate,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to a first preferred embodiment of the ninth main embodiment, the invention relates to a compound of the general formula XIII, XIV or XV, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl and

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

49 '

According to a second preferred embodiment of the ninth main embodiment, the invention relates to a compound of formula XIII, XIV or XV, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ are hydrogen,

R ⁶ is alkyl and

X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a third preferred embodiment of the ninth main embodiment, the invention relates to a compound of formula XIII, XIV or XV, wherein the base is a purine or pyrimidine base as defined above,

R ^1, R ² and R ³ independently represent hydrogen or a phosphate,

R ⁶ is alkyl and

X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

In a tenth embodiment, the present invention provides a compound of formula XVI

R ⁹ R

(XVI) • ···· »·» · * · _Λ C · ·· ·· »* · *» 50 * · · · · · · · · • * · «·

4449 where 9.4 is a purine or pyrimidine base as defined,

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl,

-C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ -N-acyl);

R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a

X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof.

According to a first preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ is alkyl, (4) R ⁷ and R ^{9 do not} SLE represent OR ^2, alkyl, alkenyl, alkynyl,

Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ and R ¹⁰ independently represent hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine, and (β) X represents 0, S, S0 ₂ or CH _2, and pharmaceutically acceptable salts or prodrugs thereof.

·· ·· • 52

According to a second preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base represents a purine or pyrimidine base as defined above; (2) R ¹ represents a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents alkyl, alkenyl, alkynyl, Br- v inyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ and ^R10 independently represent hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine, and (β) X represents 0, S, S02 or _CH2, and pharmaceutically acceptable salts or prodrugs thereof.

According to a third preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower> 33 · acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents; as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, ( 3) R ⁶ represents alkyl, alkenyl, alkynes 1, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , alkyl , alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ and R ¹⁰ represent hydrogen, (β) X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a fourth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, such as 54 is described for an aryl group, a lipid residue, including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; R ⁶ represents alkyl, alkenyl, alki nyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ and R ¹⁰ independently represent hydrogen, alkyl ( including a lower alkyl group), a chlorine, bromine or iodine atom and (β) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to a fifth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents alkyl, (4) R ⁷ and R ⁹ represent i independently OR ¹ , (5) R ⁸ and R ¹⁰ independently represent hydrogen, alkyl (including a lower alkyl group), chlorine, bromine or iodine and (6) X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or prodrugs thereof.

According to a sixth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ denotes alkyl, (4) R ⁷ and R ⁹ denote it is independently OR ² , alkyl (including lower alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower

Q alkylamino or di (lower) alkylamino, (5), R and R ¹⁰ are independently hydrogen and (6) X is 0,

S, S0 ₂ or CH _2, and pharmaceutically acceptable salts or prodrugs thereof.

ø6 ·

According to a seventh preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above; (2) R ¹ is a hydrogen atom; triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents alkyl, (4) R ⁷ and R ⁹ represent i independently OR ² , alkyl (including lower alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂ , amino, lower g

alkylamino or di (lower) alkylamino, (5), R and R ¹⁰ are independently hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine, and (β), X is 0, and pharmaceutically acceptable salts or prodrugs of these substances.

According to an eighth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized phosphate precursor, acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower alkyl alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ and R ¹⁰ are hydrogen and (β) X is O, S, SO 2 or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof.

According to a ninth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base is a purine or pyrimidine base as defined above; (2) R ¹ is a hydrogen atom; triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents alkyl (including lower and lower alkyl) alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} is independently OR ² ; (5) R ⁸ and R ¹⁰ are hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine; and (β) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to a tenth preferred embodiment of the tenth main embodiment, the invention relates to a compound of formula XVI, wherein: (1) the base represents a purine or pyrimidine base as defined above; (2) R ¹ represents a hydrogen atom; triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue, including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents alkyl (including lower alk alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} are independently OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) (5) R ⁸ and R ¹⁰ are hydrogen and (β) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to the eleventh preferred embodiment of the tenth principal embodiment, the invention relates to a compound of formula XVI, wherein (1) the base is a purine or pyrimidine base defined above, (2) R ¹ independently represents a hydrogen atom or a phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{9 is} independently OR ² , (5) R ⁸ and R ¹⁰ are hydrogen and X is O, S, SO 2 or CH ₂ as well as pharmaceutically acceptable salts or prodrugs thereof.

According to a twelfth preferred embodiment of the tenth principal embodiment, the invention relates to a compound of formula XVI, wherein (1) the base is a purine or pyrimidine base defined above, (2) R ¹ independently represents a hydrogen atom or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ independently represent OR ² , (5) R ⁸ and R ¹⁰ represent hydrogen and (6) X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof .

According to the thirteenth preferred embodiment of the tenth principal embodiment, the invention provides a compound of ¢ 0 formula XVI, wherein (1) the base is a purine or pyrimidine base defined above, (2) R ¹ independently represents a hydrogen atom or a phosphate, (3) R ⁶ denotes alkyl, (4) R ⁷ and R ⁹ independently represent oR ^2, (5) R ⁸ and R ¹⁰ are hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine, and (β) X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to the fourteenth preferred embodiment of the tenth principal embodiment, the invention relates to a compound of formula XVI, wherein (1) the base is a purine or pyrimidine base defined above, (2) R ¹ independently represents a hydrogen atom or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ independently represent OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ and R ¹⁰ are hydrogen and X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

According to further more preferred embodiments, the invention relates to a compound of formula XVI, wherein:

(1) the base is adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is a hydrogen atom and (β) ) X is O.

(1) the base is guanine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is hydrogen and (6) ) X is O.

6 (1) base is cytosine, (2) R is hydrogen, (3) R is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is hydrogen and (β) X is 0.

(1) base Yippee thymine, (2) R ¹ is a hydrogen atom; (3) R ⁶ Yippee methyl, (4) R ⁷ and R ⁹ are θ hydroxyl groups; and _R 10 is an atom hydrogen and (6) X is 0. (1) base Yippee uráčil, (2) R ¹ is a hydrogen atom; (3) R ⁶ Yippee methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and _R 10 ° is an atom hydrogen . and (β) X is 0. (1) base Yippee adenine, (2) R ¹ is a phosphate residue, (3) R ⁶

is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ are hydrogen and (6) X is O.

(1) the base is adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ is ethyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰

Yippee hydrogen atom and (6) X is 0. (1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is propyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ Yippee hydrogen atom and (β) X is 0. (1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is

butyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ are hydrogen and (6) X is O.

(1) the base is adenine, (2) R is hydrogen, (3) R is methyl, (4) R ⁷ is hydrogen and R ⁹ is hydroxyl, (5) R ⁸ and R ¹⁰ is hydrogen and ( β) X is 0.

(1) baze je adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ Yippee methyl, (4) R ⁷ a R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is an atom hydrogen and (β) X is S. (1) baze je adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ Yippee methyl, (4) R ⁷ a R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is an atom hydrogen and (β) X is S0 _second (1) baze je adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ Yippee methyl, (4) R ⁷ a R ⁹ are hydroxyl groups, (5) R ⁸ and R ¹⁰ is an atom hydrogen and (6) X is CH ₂ .

According to an eleventh embodiment of the invention, the present invention provides a compound of formula XVII

wherein the base is a purine or pyrimidine base as defined,

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and

R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ or their pharmaceutically acceptable salts or prodrugs.

According to a first preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a moiety, a lipid moiety including a phospholipid, an amino acid moiety, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower al alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (5) R ¹⁰ is hydrogen and (β) X is O, S, SO 2 or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof.

According to a second preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ phosphate (including mono-, di-hydrogen, residue or triphosphate; a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl groups, lipid residue including a phospholipid, an amino acid residue of the carbohydrate, peptide, cholesterol, or may be other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (including lower and lower alkyl) alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} is independently OR ² , (5) R ¹⁰ is hydrogen, alkyl (including a lower alkyl group), chlorine, bromine or iodine and (β) X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a third preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents; .

and · · · · ··· ♦

As described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine , NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl , O-alkenyl, chlorine, bromine, fluorine, iodine, NO 2, amino, lower alkylamino or di (lower) alkylamino, (5) R ¹⁰ represents hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine and (6) X is O, S, SO 2 or CH ₂ , and f pharmaceutically acceptable salts or precursors thereof.

According to a fourth preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl groups, a lipid residue, including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable salt. Acceptable cleavable group to form a cleavage in vivo. valuables, wherein R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , (5) R ¹⁰ is hydrogen and (β) X is O, S, SO ₂ or _CH2, and pharmaceutically acceptable salts or prodrugs thereof.

According to a fifth preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a moiety, a lipid moiety including a phospholipid, an amino acid moiety, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower and lower alkyl) alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} is independently OR ² , (5) R ¹⁰ is hydrogen, alkyl (including

68 *. «• ·

And (6) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to a sixth preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate); a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a moiety, a lipid moiety including a phospholipid, an amino acid moiety, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower alkyl) alkyl groups), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or (5) R ¹⁰ is hydrogen and (β) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

* ·· ·

»·. · · * * * * * *

«. · · · · · ·

According to a seventh preferred embodiment of the eleventh main embodiment, the invention relates to a compound of formula XVII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl groups, lipid residue including a phospholipid, an amino acid residue of the carbohydrate, peptide, cholesterol, or may be other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (including lower and lower alkyl) alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} is independently OR ² , (5) R ¹⁰ is hydrogen and (6) X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

According to the eighth preferred embodiment of the eleventh principal embodiment, the invention relates to a compound of formula XVII wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ are independently hydrogen, OR ² , alkyl (including lower alkyl, alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro); ·· »

70 'iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ¹⁰ represents a hydrogen atom, an alkyl (including a lower alkyl group), a chlorine, bromine or iodine atom; and (β) X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a ninth preferred embodiment of the eleventh principal embodiment, the invention relates to a compound of formula XVII wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ is independently OR ² , (5) R ¹⁰ is hydrogen and (β) X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof.

According to a tenth preferred embodiment of the eleventh principal embodiment, the invention relates to a compound of formula XVII wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ are independently OR ² , (5) R ¹⁰ is hydrogen and (β) X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof.

According to further more preferred embodiments, the invention relates to a compound of formula XVII, wherein:.

«MM ·: 7i / ···» ff ·· * · ffff »

9 9

9 9

9999 (1) base is adenine, (2) R ¹ is hydrogen atom methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, hydrogen atom and (β) X is 0.

(3) R ⁶ is (5) R ¹⁰ is (1) base is guani methyl, (4) R ⁷ and R ^{9 are} hydrogen and (β) X j <

n, (2) R ¹ is hydrogen, (3) R ⁶ is p pu of the hydroxyl group, (5) R ¹⁰ is

O.

(1) the base is cytosine, (2) R ¹ is a hydrogen atom, (3) R ⁶ is a methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is a hydrogen atom, and (6) O.

(1) the base is thiomethyl, (4) R ⁷ and R ^{9 are} hydrogen and (6) X is n, (2) R ¹ is hydrogen, (3) R ⁶ is an hydroxyl group, (5) R ¹⁰ is

O.

(1) the base is uracr methyl, (4) R ⁷ and R ^{9 are} a hydrogen atom, and (6) X j <

1, (2) R ¹ is a hydrogen atom, (3) R ⁶ is an hydroxyl group, (5) R ¹⁰ is

O.

(1) the base is adenine, (2) R ¹ is a phosphate residue, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (6) X is O.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is ethyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (6) X is O.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is propyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (6) X is O.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is butyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (6) X is 0.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (β) X is WITH.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (β) X is S0 ₂ .

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ° is methyl, (4) R 'and R ⁹ are hydroxyl groups, (5) R ¹⁰ is hydrogen and (6) X is CH ₂ .

According to a twelfth embodiment, the present invention provides a compound of formula XVIII

wherein the base is a purine or pyrimidine base as defined,

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester Including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or it may be another pharmaceutically acceptable leaving group which, when cleaved in vivo, yields a compound in which R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O '(alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl ), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl,

-O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ ,

-NH (lower alkyl), di (lower alkylamino),

R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X represents O, S, SO ₂ or CH ₂ or their pharmaceutically acceptable salts or prodrugs.

According to a first preferred embodiment of the twelfth main embodiment, the invention relates to a compound of the general

of formula XVIII, wherein: (1) a base is a purine or pyrimidine base as defined above; (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine-triphosphate, and a stabilized phosphate precursor), acyl including lower acyl, alkyl including a lower alkyl group, a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptide, cholesterol, or may be other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ¹ represents hydrogen or a phosphate, (3), ^R represents alkyl, (4) R ⁷ and R ⁹ are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-a alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ represents hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine and (β) X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a second preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein: the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group that cleaves in vivo to form a compound, wherein R ¹ represents a hydrogen atom or a phosphate residue, ), ^R represents an alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, N02, amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ is hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine and (6) X is O, S, SO 2 or CH ₂ as well as pharmaceutically acceptable salts or prodrugs thereof.

According to a third preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a lipid moiety, including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a residue (3) R ⁶ represents al alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO 2, amino, (5) R ⁸ is hydrogen and (β) X is O, S, SO 2 or CH ₂ , as well as pharmaceutically acceptable salts or precursors thereof.

According to a fourth preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a moiety, a lipid moiety including a phospholipid, an amino acid moiety, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower alkyl) alkyl groups), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ ,

amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl , chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (5) R ⁸ represents hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine and (β) X is O, as well as pharmaceutically acceptable salts or prodrugs thereof.

According to a fifth preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base represents a purine or pyrimidine base as defined above; (2) R ¹ represents a hydrogen atom; triphosphate and stabilized phosphate precursor), acyl including lower acyl group, alkyl including lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate residue; ⁶ represents an alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, N0 _2, amino, lower alkylamino or di (lower) alkylamino, (4) R ^7. R ⁹ is independently OR ² , (5) R ⁸ is hydrogen and (β) X is

O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts or precursors thereof.

According to a sixth preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base is a purine or pyrimidine base as defined above, (2) R ¹ is a hydrogen atom, a phosphate residue (including mono-, dine or triphosphate); a stabilized phosphate precursor), an acyl including a lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for aryl a moiety, a lipid moiety including a phospholipid, an amino acid moiety, a carbohydrate, a peptide, a cholesterol, or it may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ is a hydrogen atom or a phosphate moiety; alkyl (including lower and lower alkyl) alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ^{7 9} is independently hydrogen, OR ² , (5) R ⁸ is hydrogen, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to a seventh preferred embodiment of the twelfth main embodiment, the invention relates to a compound of formula XVIII, wherein: (1) the base is a purine or pyrimidine base as defined above; (2) R ^{1 is} as defined above; • · · ·

represents a hydrogen atom, a phosphate residue (including a mono-, dine or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, the phenyl group being optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R is ¹ is hydrogen or phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently m is hydrogen, OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di (lower) (5) R ⁸ is hydrogen and (β) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to the eighth preferred embodiment of the twelfth principal embodiment, the invention relates to a compound of formula XVIII, wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino, or &quot;&quot; Di (lower) alkylamino, (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ is hydrogen and (β) X is 0, S, S0 ₂ or CH _2, and pharmaceutically acceptable salts or prodrugs thereof.

According to a ninth preferred embodiment of the twelfth principal embodiment, the invention relates to a compound of formula XVIII, wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ is hydrogen and (6) X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts or prodrugs thereof.

According to a tenth preferred embodiment of the twelfth principal embodiment, the invention relates to a compound of formula XVIII, wherein: (1) base means a purine or pyrimidine base defined above, (2) R ¹ represents hydrogen or a phosphate, (3) R ⁶ is alkyl (4) R ⁷ and R ⁹ are independently OR ² , (5) R ⁸ is hydrogen and (6) X is O, as well as pharmaceutically acceptable salts or precursors thereof.

According to further more preferred embodiments, the invention relates to a compound of formula XVIII, wherein:

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (β) X is 0.

(1) the base is guanine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and ( β) X is 0.

(1) base is cytosine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (β) X is O.

(1) the base is thymine, (2) R ¹ is a hydrogen atom, (3) methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is a hydrogen atom, and (6) X is O.

(1) the base is uracil, (2) R ¹ is a hydrogen atom, (3) methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is a hydrogen atom, and (β) X is O.

(1) the base is adenine, (2) R ¹ is a phosphate residue, is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) a hydrogen atom, and (β) X is O.

R ⁶ is

R ⁶ is

R ^a is (3) R ^fc (1) the base is adenine, (2) R ¹ is a hydrogen atom, (3) R ⁶ is ethyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is and (6) X is O.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is propyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (β) X is O.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁵ is butyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (6) X is O.

4 (1) base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups , (5) R ⁸ is hydrogen and (β) X is S.

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (6) X is S0 ₂ .

(1) the base is adenine, (2) R ¹ is hydrogen, (3) R ⁶ is methyl, (4) R ⁷ and R ⁹ are hydroxyl groups, (5) R ⁸ is hydrogen and (β) X is CH ₂ .

The β-D- and β-L-nucleosides of the invention have the ability to inhibit HCV polymerase. These nucleosides can be tested for in vitro potency by the following procedures. The spectrum of activity can be determined in comparison with known substances.

In one embodiment, the activity of compounds measured by the concentration of compound which is required to reduce the plaque number of the virus in vitro by 50%, ie a _EC50 value for that substance. In preferred embodiments, the compounds have an EC ₅ of less than 15 or 10 pmol as measured by Ferrari et al., Jnl. of Vir., 73: 1649-1654, 1999, Ishii et al., Hepatology, 29: 1227-1235, 1999, Lohman et al., Jnl. of Bio. Chem., 274: 10807-10815, 1999 or Yamashita et al., Jnl. of Bio. Chem., 273: 15479-15486 (1998).

The active ingredients may be administered in the form of any salt or prodrug from which the active ingredient is released, directly or indirectly, or may be used directly:

• The active substance. Examples include pharmaceutically acceptable salts, and the precursor compound which has been alkylated or acylated at the 5 'position of the purine or pyrimidine base is a pharmaceutically acceptable precursor. Said modifications may affect the biological activity of the compound and in some cases even increase this activity. This can be readily demonstrated by the preparation of the salt or precursor and subsequent testing for antiviral activity in the manner described or in another known manner.

II. Definition

The term alkyl, as used herein, means a straight, branched, or cyclic saturated primary, secondary or tertiary hydrocarbon radical having typically 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl,

2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. Groups which may be substituted include hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, optionally with a protective group. , for example, by the method of Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

• ·· ·· · · · · ·

Lower alkyl means a straight or branched chain alkyl of 1 to 4 carbon atoms, optionally cyclic alkyl, substituted or unsubstituted. Unless explicitly stated otherwise, lower alkyl is more preferred when alkyl is a suitable usable group. Similarly, when alkyl or lower alkyl is a suitable group, unsubstituted alkyl or lower alkyl is more preferred.

Alkylamino or arylamino means an amino group having 1 or 2 alkyl or aryl substituents. A protecting group is a group that binds to an oxygen, nitrogen, or phosphorus atom to prevent further reaction or other purpose. A wide variety of protecting groups are known, particularly for oxygen and nitrogen atoms for organic synthesis purposes.

The term aryl, unless expressly stated otherwise, means phenyl, biphenyl or naphthyl, preferably phenyl.

The term includes both unsubstituted and substituted groups. The aryl group may be substituted with one or more groups selected from hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate residues, optionally optionally a protective group, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term alkaryl or alkylaryl means alkyl groups with aryl substituents. The term aralkyl or ¢ 5: arylalkyl includes aryl groups with alkyl substituents.

Halogen is understood to mean chlorine, bromine, iodine and fluorine throughout the application.

The term purine or pyrimidine base includes, for example N ⁶ -alkylpuriny, ^with N -acylpuriny (wherein acyl is C (0) (alkyl, aryl, alkylaryl, or arylalkyl), ^with -benzylpurin N, N -halogenpurin ^6, N ⁶ -vinylpurin, -acetylenpurin N ^6, N -acylpurin ^with N -hydroxyalkylpurin ^6, N ⁶ -thioalkylpurin N -alkylpuriny ^2, N ² -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, including β-aza pyrimidine 6-azacytosine, 2- and / or

4-mercaptopyrimidine, uracil, 5-halouracil inclusive

5-fluorouracil, C ⁵ -alkylpyrimidiny, -benzylpyrimidiny ^{C5, C5} -halogenpyrimidiny, -vinylpyrimidiny ^{C5, C5} -acetylenpyrimidiny, -acylpyrimidiny ^{C5, C5} -hydroxyalkylpurin, ^C5 -amidopyrimidin,

-Kyanopyrimidin C ^5, C ⁵ -nitropyrimidin, C ⁵ -aminopyrimidine, N ² -alkylpuriny, N ² -alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, for example, guanine, adenine, hypoxanthine,

2, β-diaminopurine and 6-chlorpurine. Functional oxygen and nitrogen atoms in these bases can be protected if necessary. Suitable protecting groups are generally known and include, for example, trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, trityl, alkyl and acyl groups such as acetyl, propionyl, methanesulfonyl and p-toluenesulfonyl.

• · · ·

Acyl means a carboxylic acid ester in which the non-carbonyl group is selected from straight, branched and cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl such as benzyl, aryloxyalkyl such as phenoxymethyl, aryl such as phenyl optionally substituted with chlorine , bromine, fluorine, iodine, C 1 -C 4 alkyl or alkoxy, sulfonate such as alkyl or aralkylsulfonyl including methanesulfonyl, mono-, di- or triphosphate, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl such as dimethyl-tert-butylsilyl or diphenylmethylsilyl. The preferred meaning of the aryl group in these esters is phenyl. Lower acyl means an acyl group containing a lower alkyl group.

By &quot; substantially free &quot; is meant a nucleoside which contains 85 to 90, preferably 95 to 98, and particularly 99 to 100% by weight of said enantiomer of said nucleoside. In a preferred embodiment, the compounds of the invention are substantially enantiomer-free.

The term "isolated" refers to a nucleoside containing at least 85 to 90, preferably 95 to 98, and in particular 99 to 100% by weight nucleosides, the remainder being other chemical substances or enantiomers.

The term "independently" means that said substituent or group is used independently for a particular use. That is, for example, in a compound R''XYR '', where R '' independently represents a carbon or nitrogen atom, both R '' may be a carbon or nitrogen atom or one of them is a carbon atom and the other a nitrogen atom.

«· .E ?: *

The term host during the application means a unicellular or multicellular organism in which replication of the virus, including cell lines and animals, including humans, may occur. The host may carry part of the hepatitis C virus genome, wherein the replication or function of the genome may be altered by the action of the compounds of the invention. The term host particularly includes infected cells, cells transfected with all or part of the HCV genome, and animals, especially primates including chimpanzees, as well as humans. In most cases, the host is human. Veterinary applications are also contemplated, for example in the case of chimpanzees.

As used herein, the term "pharmaceutically acceptable salt or precursor" refers to any pharmaceutically acceptable form (e.g., ester, phosphate, ester salt, or related group) of a nucleoside compound from which the nucleoside compound is released upon administration to a patient. The pharmaceutically acceptable salts may be derived from pharmaceutically acceptable inorganic or organic bases and acids. Examples are alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, which are commonly used in pharmacy. Pharmaceutically acceptable precursors are compounds that are metabolized in the host, for example, hydrolyzed or oxidized to form a compound of the invention. Typical examples of precursors are substances which carry a biologically labile protecting group on the functional group of the active substance. Thus, they are subject to oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation or dephosphorylation to form the active compound. The free compounds of the invention have antiviral activity against HCV or are metabolized to compounds having such activity.

III. Use of salts or precursors of nuclides

In cases where the compounds are sufficiently alkaline or acidic to form stable, nontoxic salts with acids or bases, administration of these compounds in the form of pharmaceutically acceptable salts may be most appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts providing a physiologically acceptable anion, such as tosylate, methanesulfonate, acetic, citric, malonic, tartaric, succinic, benzoic, ascorbic, α-ketoglutaric and α-glycerophosphoric salts. . Salts with inorganic acids such as sulfates, nitrates, bicarbonates and carbonates can also be formed.

Pharmaceutically acceptable salts may be prepared using conventional procedures known in the art, for example by reacting an alkaline compound such as an amine with a suitable acid with a physiologically acceptable anion. It is also possible to form alkali metal salts of carboxylic acids, for example sodium, potassium or lithium salts or alkaline earth metals, such as calcium salts.

Any of the above-described nucleosides can be administered as a nucleotide precursor to enhance potency, bioavailability, stability, or to achieve other

89;

changes in nucleoside properties. A variety of ligands for the formation of these precursors are known. For example, nucleotide stability may be enhanced by alkylation, acylation, or other lipophilic modification of the mono-, di-, or triphosphate group of the nucleoside. Examples of substituents to replace one or more hydrogen atoms on a phosphate group include alkyl, aryl, steroid groups, carbohydrate residues including sugars, 1,2-diacylglycerol, and alcohols. Many of these are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995), 1-17. Any of these groups can be used in combination with nucleosides to achieve the desired effect.

The active nucleosides may also be in the form of a 5'-lipid phosphoether or a 5'-lipid ether, as described in Kucera, L. S., N. Iyer, E. Leake,

A. Raben, Modet E. K., D. L. W., and C. Piantadosi, 1990, Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induction defective virus formation, AIDS Res. Hum. Retro Viruses 6:

491-501, Piantadosi, C., J. Marasco, C.J., S.L. MorrisNatschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S., Ishaq, L.S. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi, and E.J. Modest. 1991, Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity, J. Med. Chem. 34: 1408-1414, Hosteller, K. Y., D. D. Richman, D. A. Carson, L. M. Stuhmiller, G. m. T. van Wijk, and H. van den Bosch. 1992, Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, and the lipid prodrug of 3'-deoxythymidine, Antimicrob. Agents Chemother. 36: 2025-2029, Hosetler, K.Y., L.M. Stuhmiller, Η. B.

• »£ 0

Lenting, Η. van den Bosch, and D. D. Richman, 1990. Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides. J. Biol. Chem. 265: 61127.

Examples of patent documents describing suitable lipophilic substituents that can be covalently linked to a nucleoside, preferably at the 5'-OH position, are US 5149794 of September 22, 1992 (Yatvin et al.), US 5194654 of 16. U.S. Pat. No. 5223263, issued June 29, 1993 (Hostetler, et al.), U.S. Pat. No. 5,256,641, October 26, 1993 (Yatvin, et al.), U.S. Pat. No. 5,411,947, May 2, 1995 (Hostetler, et al.), U.S. Pat. On Oct. 31, 1995 (Hostetler et al.), US 5543389;

6 August 1996 (Yatvin et al.), US 5543390 of 6 August 1996 (Yatvin et al.), US 5543391 of 6 August 1996 (Yatvin et al.) And US 5554728 of 10 September 1996 (Basava et al.). Lipophilic substituents which can be attached to the nucleosides of the invention and the resulting products are described in International Applications WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 350287, EP 93917054.4 and WO 91/19721.

IV. Combination and alternative treatment

It has been shown that after prolonged treatment with antiviral agents, HCV variants may develop which are resistant to the action of these agents. Typically, this resistance occurs by mutation of an enzyme encoding gene involved in virus replication. The activity of anti-HCV agents can be prolonged, enhanced or regenerated by administering such agents in combination with a second and optionally a third antiviral agent, or alternatively, with an agent that causes a different type of mutation. It is also possible to vary the pharmacokinetics of the active substances, their biological distribution or other parameters of the active substances by combination or alternative treatments. In general, combination therapy is more advantageous than alternate therapy because of the simultaneous damage of the virus at two sites.

Non-limiting examples of antiviral agents that can be used in combination with the compounds of the invention include the following groups of agents:

(1) Interferon and / or ribavirin according to the publications (Battaglia, A. M. et al., Ann. Pharmacother, 34: 487494, 2000), Berenguer, M. et al., Antivir. Ther. 3 (Suppl. 3): 125-136 (1998).

2. Substrate NS3 Protease Inhibitors of Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998, Attwood et al., Antiviral Chemistry and Chemotherapy 10.259-273, 1999, Attwood et al., Preparation and use of amino acid derivatives as antiviral agents, DE 19914474, Tung et al., Inhibitors of serine proteases, paricularly hepatitis C virus NS3 protease, PCT WO 98/17679 including α-ketoamides and hydrazinureas and inhibitors that terminate with an electrophilic group, for example the boronic acid residue or phosphonate according to Llinas -Brunet et al., Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.

3. Subostate-independent inhibitors, for example the 2,4,6-trihydroxy-3-nitrobenzamide derivative according to Sudo K. et al., Biochemical and Biophysical Research

Communications, 238: 643-647, 1997, Sudo, K. et al., Antiviral Chemistry and Chemotherapy, 9: 186, 1998, including RD3-4082 and RD3-4078, the first of which is a substituted 14-carbon amide the other of which contains a p-phenoxyphenyl group.

4. Thiazolidine derivatives which can be shown to be inhibited by reverse phase HPLC with the NS3 / 4A fusion protein and NS5A / 5B substrate according to Sudo K. et al., Antiviral Research, 32: 9-18, 1996, the specific compound being RD- 1-6250 containing a cinnamic acid residue substituted with a long alkyl chain as well as RD4 6205 and RD4 6193.

5. Thiazolidines and benzanilides according to Kakiuchi N. et al., J. EBS Latters 421: 217-220, Takeshita N. et al., Analytical Biochemistry 247: 242246, 1997.

6. Phenanthrenchinone with anti-HCV protease activity in SDS-PAGE and autoradiography, isolated from Streptomyces sp. Sch 68631 according to CHu, M. et al., Tetrahedron Letters 37: 7229-7232, 1996 and Sch 351633, isolated from Penicillus griseofulvum, is effective in the scintillation assay of Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949 -1952.

7. Selective NS3 inhibitors based on the elgin c macromolecule isolated from the pore according to Qasim M. A. et al., Biochemistry 36: 1598-1607, 1997.

93. ’

8. HCV Helicase Inhibitors of Diana G. D. et al. Compounds, compositions and methods for the treatment of hepatitis C, US 5633358, Diana G. D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT

WO 97/36554.

9. HCV polymerase inhibitors, for example nucleotide analogues, gliotoxin according to Ferrari R. et al., Journal of Virology 73: 1649-1654, 1999 and the natural product cerulenin according to Lohmann V. et al., Virology 249: 108-118, 1998.

10. Antisense phosphothioate oligodeoxynucleotides S-ODN, complementary to the extension of the sequence in the 5'-non-coding region of the HCV NCR according to Alt M. et al., Hepatology 22: 707-717, 1995, or nucleotides 326-348, containing the 3'-end of NCR and nucleotides 371-388, deposited in the IICV RNA core coding region of Alt M. et al., Archives of Virology 142: 589-599, 1997,

Galderisi U. et al., Journal of Cellular Physiology 181: 251-257, 1999.

11. Inhibition of IRES-dependent translation according to Ikeda N. et al., Agent for the prevention and treatment of hepatitis C, JP-08268890, Kai Y. et al., Prevention and treatment of viral diseases, JP-10101591.

12. Nuclease-resistant ribozymes according to Maccjak,

D. J. et al., Hepatology 30, abstract 995, 1999, a

13. Various other substances, for example 1-aminoalkylcyclohexanes according to US 6034134 (Gold et al.), Alkyl lipids according to US 5922757 (Chojkier et al.), Squalene, amantadine, bile acids according to US 5846964 (Ozeki et al.), N acid. - (phosphonoacetyl) -L-aspartic according to US 5830905 (Diana et al.), benzenedicarboxamides according to US 5633388 (Diana et al.), polyadenylic acid derivatives according to US 5496546 (Wang et al.), 2 ', 3'-dideoxyinosine according to US 5026687 ( Yarchoan et al.) And benzimidazoles of US 5891874 (Colacino et al.).

V. Pharmaceutical compositions

A host infected with HCV or a gene fragment thereof may be treated by administering an effective amount of the compound or a pharmaceutically acceptable salt or precursor thereof together with a pharmaceutically acceptable carrier or diluent. The usual host is human. The active materials may be administered by any suitable means, for example orally, parenterally, intravenously, intradermally, subcutaneously or topically in liquid or solid form.

A preferred dose of active ingredient will be in the range of 1 to 50 mg / kg body weight per day, preferably a dose of 1 to 20 mg / kg and especially 0.1 to 100 mg / kg. The effective dose of a pharmaceutically acceptable salt or precursor can be calculated based on the molecular weight of the nucleoside. When the salt or precursor itself is active, the active ingredient may be determined by the weight of the salt or precursor or by other conventional methods.

The active compounds are administered in suitable dosage forms, which may contain from 7 to 3000, preferably from 70 to 3000

Usually

1400 mg of active ingredient in a single dose, administered an oral dose of 50 to 1000 mg.

Ideally, the active ingredient should be administered to achieve a peak plasma concentration in the range of 0.2 to 70, preferably 1.0 to 10 μΜ. This can be achieved, for example, by intravenous administration of a 0.1 to 5% solution of the active compound, optionally in saline.

The concentration of the active ingredient in the pharmaceutical composition will depend on its rate of absorption, inactivation and excretion, and other known factors. It should be noted that dosages will also depend on the severity of the disease being treated. It will also be appreciated that individual dosages need to be adjusted over time as needed for the individual patient, so that the dosages given are exemplary only and are not intended to limit the practice of the compounds of the invention. The active ingredient may be administered in a single daily dose or may be divided into divided doses administered at different intervals throughout the day.

Oral administration is the preferred mode of administration. For oral administration, an inert diluent or other edible carrier is usually used as the carrier. The resulting composition may be a gelatin capsule or a compressed tablet. Thus, for oral administration, the active ingredient is mixed with excipients and then compressed into tablets or filled into capsules. Suitable binders and / or other excipients may be added.

Tablets, pills, capsules and the like may contain the following excipients: binders such as microcrystalline cellulose, gum tragacanth or gelatin, a filler such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch, glidants such as magnesium stearate, Sterotes or colloidal silica, sweeteners such as sucrose or saccharin and flavorings such as menthol, methyl salicylate or orange flavor. In the case of a capsule, the capsule may additionally contain a liquid carrier such as an oil. In addition, these dosage forms may contain other materials which alter their physical form, for example, coatings of sugar, shellac or other enteric agents.

The active ingredients may also be administered in the form of an elixir, suspension, syrup, wafer, chewing gum or the like. The syrup may contain sucrose as a sweetening agent and may additionally contain preservatives, colorants and various flavorings.

The active ingredient, or a pharmaceutically acceptable salt or precursor thereof, may also be mixed with other active ingredients which do not interfere with the desired effect or with materials that may supplement the effect, such as antibiotics, antifungal agents, anti-inflammatory agents or other antiviral agents including other nucleosides. Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerol, polyethylene glycol or other synthetic solvents, antibacterials such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for adjusting the osmotic pressure such as sodium chloride or dextrose. Formulations for parenteral administration may be presented in ampoules or may be prefilled syringes or glass or plastic vials containing multiple unit doses.

For intravenous administration, the preferred carrier is saline, optionally with phosphate buffered saline, PBS.

In a preferred embodiment, the active ingredient-containing pharmaceutical compositions are formulated so as to protect the active ingredient from rapid elimination from the body, for example, controlled release formulations, including implants and microcapsules. Biodegradable biocompatible polymers can also be used. Examples are ethylene vinyl acetate, polyanhydrides, polyglycolic acids, collagen, polyorthoesters and polylactic acid. Methods for making such compositions are known. These materials are also commercially available from Alza Corporation.

Liposomal suspensions that contain liposomes targeted to infected cells with monoclonal antibodies against viral antigens are also a preferred pharmaceutically acceptable carrier. These liposomal suspensions may be prepared in a manner known per se, for example in US 4522811. For example, lipids such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine and arachidoylphosphatidylcholine or cholesterol may be dissolved in an inorganic solvent, which then evaporates and leaves a thin film on the surface. An aqueous solution of the active ingredient or its monophosphate, diphosphate and / or triphosphate is then added to the container provided with such a coating. The container is then shaken by hand to release the lipid material from the walls of the container and disperse to form a liposome suspension.

VI. Method for producing active substances

The nucleosides of the invention can be synthesized by any known method. For example, it may be an alkylation of an appropriately modified sugar with subsequent glycosylation or glycosylation with subsequent alkylation. Some preferred general embodiments of the methods for obtaining nucleosides of the invention will be set forth below.

A. Synthesis of 1'-C-branched nucleosides

These substances can be expressed by the following structure:

where

BASE means a purine or pyrimiding base as defined above;

R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl,

-C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a

R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁶ is alkyl, chloroalkyl, bromoalkyl, fluoroalkyl or iodoalkyl, for example CF ₃ , alkenyl or alkynyl (allyl), and X is O, S, SO ₂ or CH ₂ .

1. Preparation of the resulting compound from lactone

A key starting material for this process is an appropriately substituted lactone. These lactones are commercially available or can be prepared by any known method including standard epimerization, substitution and cyclization. The lactone may be protected by suitable protecting groups, preferably an acyl or silyl group according to the method of Greene et al.

The protected lactone can then be coupled to a suitable binding agent, for example a carbon-based organometallic nucleophilic substance, such as Grignard reagent, organic lithium compounds, dialkyl copper lithium compounds, or R ⁶ -SiMe 3 in TBAF in the presence of a suitable non-protic solvent at a suitable temperature yields a 1'-alkylated sugar.

The optionally activated sugar can then be coupled on a known basis, for example according to Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base using a Lewis acid, e.g. in an appropriate solvent at a suitable temperature.

The nucleoside may then be deprotected in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, a 1'-C-branched ribonucleoside may be required. The synthesis of this substance is shown in Scheme 1. It may also be

101 ·· * *>

• deoxyribonucleoside required. To obtain these nucleosides, the ribonucleoside formed may optionally be protected in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl group can be activated to facilitate reduction, such as the so-called Barton reduction.

Scheme 1

activation

1) binding

2) deprotection, if any

RO.

I, R OR ²

BASE 1) ^H0 protection, if any

BASE

HIM.

2) possible reduction or deprotection

BASE

O-

OH

OH OH

1Q2

2. Alternative procedure for the preparation of 1 '-C-branched nucleosides

A key starting material for this process is an appropriately substituted hexose. These materials are supplied or can be prepared in a manner known per se, including standard epimerization, for example by treatment with a base, substitution and coupling. Hexose can be selectively protected to give the appropriate hexafuranose according to Townsend, Chemistry of Nucleosides and Nucleotides,

Plenum Press, 1994.

The 1'-hydroxyl group may optionally be activated to a suitable leaving group, for example to an acyl group or a chlorine, bromine, fluorine or iodine atom by acylation or halogenation. The optionally activated sugar can then be coupled on a base known in the art by Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate. a suitable solvent at a suitable temperature. The halogenated sugar may be coupled to a silylated base in the presence of trimethylsilyl triflate.

When the 1'-CH 2 -OH group is protected, it can be selectively deprotected in a known manner. The resulting primary hydroxyl group can then be substituted to provide various C-branched nucleosides. For example, a primary hydroxyl group can be reduced to a methyl group using a suitable reducing agent. The hydroxyl group can be activated prior to the reduction to facilitate this reaction.

. Reakce)))))) tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato tato Bartoňova redukce. The primary hydroxyl group can also be oxidized to an aldehyde and the resulting product then bind to nucleophilic compound such as a Grignard reagent, an organolithium, lithium dialkylcopper or R ⁶ -SiMe 3 in TBAF using an appropriate non-protic solvent at a suitable temperature.

In a specific embodiment, a 1'-C-branched ribonucleoside may be required. The synthesis of this compound is shown in Scheme 2 below. Deoxyribonucleoside may also be required. In this case, the ribonucleoside formed may optionally be protected in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH group may be reduced with a suitable reducing agent. Optionally, the 2'-hydroxy group can be activated to facilitate reduction.

»· * *» - «-». «- * *» *

The L-enantiomers corresponding to the compounds of the invention may also be prepared by the method of Reaction Schemes 1 or 2, starting from the corresponding L-sugar or L-enantiomer of the nucleoside.

B. General synthesis of 2'-C-branched nucleosides

These substances can be expressed by the following structure:

where

BASE means a purine or pyrimidine base as defined above,

R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NK ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ,

R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ optionally form a bond and

R ¹ and R ² independently represent Acom atom, a phosphate (including mono-, di- or triphosphate and a stabilized phosphate precursor · *), acyl including lower acyl,

1 * 05.

alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, lipid residue including phospholipid, amino acid residue, carbohydrate , a peptide, a cholesterol, or another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ or R ^{2 is} independently hydrogen or phosphate,

^R denotes alkyl, chloroalkyl, bromoalkyl, or jodalkyl fluoroalkyl, for example CF _3, alkenyl or alkynyl (allyl) and X represents O, S, S0 ₂ or CH _second

Glycosylation of a base with an appropriately modified sugar

A key starting material for this process is an appropriately substituted sugar with 2'-OH and 2'-H, with an appropriate leaving group LG, for example an acyl group or a chlorine, bromine, fluorine or iodine atom. The sugars are commercially available or can be prepared in a known manner, for example by standard epimerization, substitution, oxidation and reduction. The substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to form a

2'-modified sugar. The oxidizing agent to be used is, for example, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (chromium dipyridine oxide), Corey reagent (pyridinium chlorochroman), pyridinium dichloromethane, dichromic acid, potassium permanganate, manganese dioxide, ruthenium oxide, or a catalyst can be used. for transmission

0 »

000 ··· »phase, such as chromic acid or permanganate, polymer-deposited, chlorine-pyridine, hydrogen peroxide and ammonium molybdate, NaBrC> 2-CAN, NaOCl in HOAc, copper chromide, copper oxide, Raney nickel, palladium acetate , Meerwin-Pondorf-Verley reagent (aluminum tert-butoxide with another ketone) and N-bromosuccinimide.

Coupling of an organometallic carbon nucleophilic compound such as a Grignard reagent, an organolithium compound, a dialkyl copper lithium compound or R ⁶ -SiMe ₃ in TBAF to a ketone in an appropriate non-protic solvent at a suitable temperature affords a 2'-alkylated sugar. The alkylated sugar may optionally be protected using an appropriate protecting group, preferably an acyl or silyl group, in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley &amp;

The optionally protected sugar is then coupled on a known basis, for example according to Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, the acylated sugar is bound to a silylated base using a Lewis acid such as tin (II) chloride, titanium tetrachloride or trimethylsilyl triflate in a suitable solvent at a suitable temperature. The halogenated sugar may be coupled to a silylated base in the presence of trimethylsilyl triflate.

The nucleoside may then be deprotected in a manner known per se, for example, according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, a 2'-C-branched ribonucleoside may be required. The synthesis of this compound is shown in Scheme 3. If a deoxyribonucleoside is desired, the ribonucleoside formed can be protected, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then reduced. 2'-OH with a suitable reducing agent. The 2'-hydroxyl group can be activated to facilitate the reaction, referred to as Barton reduction.

Scheme 3

1) R ⁶ -M ^r! O.

> -

2) possible protection

OR ^{1 2} OR ³

1) binding

2) Deprotection, if any

1) protection, if any

2) possible reduction *

! optional; deprotection i

BASE

OH

2. Modification of the preformed nucleoside

The key material for this process is an appropriately substituted nucleoside with 2'-OH and 2'-H groups. These nucleosides are supplied or can be prepared by standard procedures. The nucleoside may be protected by suitable protecting groups, preferably acyl or silyl groups, in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to provide a 2'-modified sugar. The oxidizing agent to be used is, for example, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (chromium dipyridine oxide), Corey reagent (pyridinium chlorochroman), pyridinium dichloromethane, dichromic acid, potassium permanganate, manganese dioxide, ruthenium oxide, or a catalyst can be used. for phase transfer, for example, polymer-supported chromic acid or permanganate, a mixture of chlorine and pyridine, a mixture of hydrogen peroxide and ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromide, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf -Verley's reagent (aluminum tert-butoxide with another ketone) and N-bromosuccinimide.

The nucleoside may then be deprotected, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

• iU9

In a specific embodiment, a 2'-C-branched ribonucleoside may be required. The synthesis of this compound is shown in Scheme 4. If a deoxyribonucleoside is desired, the ribonucleoside formed is optionally protected in a known manner, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition , 1991, whereupon the 2'-OH can be reduced with a suitable reducing agent. The 2 ' -hydroxyl group can be activated to facilitate reduction, referred to as Barton reduction.

Scheme 4

R * O

BASE

STEED'

STEED

1) protection, if any

2) any reduction

eventual deprotection

OH

Á * 0

In another possible embodiment, L-enantiomers corresponding to the compounds of the invention may be required. These compounds can be prepared by the same general procedures except that the corresponding L-sugars or L-enantiomers of nucleosides are used as starting materials.

C. General synthesis of 3'-C-branched nucleosides

These substances can be expressed by the following structure:

where

BASE means a purine or pyrimidine base as defined above,

R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2z

R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and

R @ ¹ and R @ ² independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized).

phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group , a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue,

R ⁶ is alkyl, chloroalkyl, bromoalkyl, fluoroalkyl or iodoalkyl, for example CF ₃ , alkenyl or alkynyl (allyl), and X is O, S, SO ₂ or CH ₂ .

Glycosylation of a base with an appropriately modified sugar

A key starting material for this process is an appropriately substituted sugar with 3'-OH and 3'-H, with an appropriate leaving group LG, for example an acyl group or a chlorine, bromine, fluorine or iodine atom. This sugar is supplied or can be prepared by known methods such as epimerization, substitution, oxidation and reduction. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to form the 3'-modified sugar. The oxidizing agent to be used is, for example, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (chromium dipyridine oxide), Corey reagent (pyridinium chlorochroman), pyridinium dichloromethane, dichromic acid, potassium permanganate, manganese dioxide, ruthenium dioxide, or

112 a phase transfer catalyst such as chromic acid or permanganate, polymer deposited, a mixture of chlorine and pyridine, a mixture of hydrogen peroxide and ammonium molybdate, NaBrCQ-CAN, NaOCl in HOAc, copper chromide, copper oxide,

Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum tert-butoxide with another ketone) and N-bromosuccinimide.

Coupling of an organometallic carbon nucleophilic compound such as a Grignard reagent, an organolithium compound, a lithium dialkyl copper compound or an R ⁶ -SiMe ₃ in TBAF to a ketone in an appropriate non-protic solvent at an appropriate temperature affords a 3'-C-branched sugar. The sugar may optionally be protected using an appropriate protecting group, preferably an acyl or silyl group, in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar is then coupled on a known basis, for example according to Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, the acylated sugar is bound to a silylated base using a Lewis acid such as tin (II) chloride, titanium tetrachloride or trimethylsilyl triflate in a suitable solvent at a suitable temperature. The halogenated sugar may be coupled to a silylated base in the presence of trimethylsilyl triflate.

The nucleoside may then be deprotected in a manner known per se, for example, according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

. : ιΐ3

In a specific embodiment, a 3'-C-branched ribonucleoside may be required. The synthesis of this compound is shown in Scheme 5. If a deoxyribonucleoside is desired, the ribonucleoside formed can be protected, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then reduced. 2'-OH with a suitable reducing agent. The 2'-hydroxyl group can be activated to facilitate the reaction, referred to as Barton reduction.

Scheme 5

HIM-

LG

1) R protection, if any

-> -

1) R-M

HO OH 2) oxidation of OOR ^;

2) protection, if any

OR ² OR ³

BASE

H <

OH

2. Modification of preformed nucleosides

The key material for this process is an appropriately substituted nucleoside with 3'-OH and 3'-H groups. These nucleosides are supplied or can be prepared by standard procedures. The nucleoside may be protected by suitable protecting groups, preferably acyl or silyl groups, in a manner known per se, for example according to Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2'-modified sugar. The oxidizing agent to be used is, for example, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (chromium dipyridine oxide), Corey reagent (pyridinium chlorochroman), pyridinium dichloromethane, dichromic acid, potassium permanganate, manganese dioxide, ruthenium dioxide, or a catalyst can be used. for phase transfer, for example, polymer-supported chromic acid or permanganate, a mixture of chlorine and pyridine, a mixture of hydrogen peroxide and ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromide, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf -Verley's reagent (aluminum tert-butoxide with another ketone) and N-bromosuccinimide.

The nucleoside may then be deprotected, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

: ιΐ5

• # • • # # # # # # #

In a specific embodiment, a 3'-C-branched ribonucleoside may be required. The synthesis of this compound is shown in Scheme 6. If a deoxyribonucleoside is desired, the ribonucleoside formed is optionally protected in a known manner, for example, by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Edition. , 1991, whereupon the 2'-OH can be reduced with a suitable reducing agent. The 2'-hydroxyl group can be activated to facilitate reduction, which is referred to as Barton reduction.

Scheme 6

eventual deprotection

R0 _xr 6

OR ^X

BASE 1) Possible protection

BASE

2) any reduction

O

OH OH possible deprotection

HO ^ _r 6

BASE

O-

OH · ♦ »

In another possible embodiment, L-enantiomers corresponding to the compounds of the invention may be required. These compounds can be prepared by the same general procedures except that the corresponding L-sugars or L-enantiomers of nucleosides are used as starting materials.

The following examples are intended to illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1. Preparation of 1'-C-methylriboadenine via 6-amino-9- (1-deoxy-β-D-psicofuranosyl) purine

The compound may also be prepared as described in J. Farkas and F. Sorm, Nucleic acid components and their analogues. XCIV. Synthesis of 6-amino-9- (1-deoxy-β-D-psicofuranosyl) purine, Collect. Czech. Chem. Commun. 1967, 32, 2663-2667, by J. Farkas, Collect. Czech. Chem. Commun. 1966, 31, 1535), Scheme 7,

6-benzamidopurine p -TolO-i _n ? ^{r of} copper copper ±

Diagram

p-ToIO Op-Tol

In a similar manner, but using the appropriate sugar and the appropriate pyrimidine or purine base, the nucleosides of Formula I shown in the following table can be prepared.

• · · · of///

(D where

R ¹ R ² R ² x ¹ X ¹ Y H 1 H H H H H H H H H H nh ₂ H H H H H NH-cyclopropyl H H H H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH H H H H H About me H H H H H OEt H H H H H O-Cyclopropyl H H H H H O-acetyl H H H H H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F H H H H H Cl H H H H H Br H H H H H AND monophosphate H H H H nh ₂ monophosphate H H H H NH-acetyl monophosphate H [ H H H NH-cyclopropyl

• · · · · ·

R ¹ R ² R ³ X ¹ X ² Y monophosphate H H H H NH-methyl monophosphate H H H H NH-ethyl monophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate H H H H About me monophosphate H H H H OEt monophosphate H H H H O-Cyclopropyl monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H S-cyclopropyl monophosphate H H H H F monophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H H AND diphosphate H H H H nh ₂ diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphate H H H H About me diphosphate H H H H OEt diphosphate H H H H O-Cyclopropyl diphosphate H H H H SH diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H H Cl

22.0

R ¹ R ² R ² X ¹ X ² Y . diphosphate H H H H Br diphosphate H H H H AND triphosphate H H H H nh ₂ triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H About me triphosphate H H H H OEt triphosphate H H H H O-Cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H H SEt triphosphate H H H H S-cyclopropyl triphosphate H H H H F triphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H AND monophosphate monophosphate monophosphate H H nh ₂ monophosphate monophosphate monophosphate H H NH-cyclopropyl monophosphate monophosphate monophosphate H H OH monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H H NH ₂ diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H NH ₂

Μ

R ¹ R ² R ³ x ¹ - X ² Y triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F H nh ₂ H H H F H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH ₂ H H H Cl H NH-cyclopropyl H H ' H Cl H OH H H H Cl H F H H H Cl H Cl H H H Br H nh ₂ H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br H Cl H H H nh ₂ H nh ₂ H H H nh ₂ H NH-cyclopropyl H H H nh ₂ H OH H H H nh ₂ H F H H H nh ₂ H Cl H H H SH H NH ₂ H H H SH H NH-cyclopropyl H H H SH H OH H H H SH H F H H H SH H Cl acetyl H H H H NH ₂ acetyl H H H H NH-cyclopropyl

42Z

R ¹ R ² R ³ X ¹ X ¹ Y acetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H nh ₂ acetyl H H F H NH-cyclopropyl acetyl H H F H OH acetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H nh ₂ H acetyl acetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetyl acetyl acetyl H H nh ₂ acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H H OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H H Cl monophosphate acetyl acetyl H H nh ₂ monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetyl acetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetyl acetyl H H NH ₂ diphosphate acetyl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H nh ₂ triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H , H OH

12.Z

R ¹ R ² R ³ X ¹ X ² Y triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H nh ₂ H H H H H nh ₂ nh ₂ H H H H nh ₂ NH-cyclopropyl H H H H nh ₂ NH-methyl H H H H nh ₂ NH-ethyl H H H H nh ₂ NH-acetyl H H H H nh ₂ OH H H H H nh ₂ About me H H H H nh ₂ OEt H H H H nh ₂ O-Cyclopropyl H H H H nh ₂ O-acetyl H H H H nh ₂ SH H H H H nh ₂ SMe H H H H nh ₂ SEt H H H H nh ₂ S-cyclopropyl H H H H nh ₂ F H H H H nh ₂ Cl H H H H nh ₂ Br H H H H nh ₂ AND monophosphate H H H nh ₂ nh ₂ monophosphate H H H nh ₂ NH-acetyl monophosphate H H H nh ₂ NH-cyclopropyl monophosphate H H H nh ₂ NH-methyl monophosphate H H H nh ₂ NH-ethyl monophosphate H H H nh ₂ OH monophosphate H H H nh ₂ O-acetyl monophosphate H H H nh ₂ About me monophosphate H H H nh ₂ OEt monophosphate H H H. · nh ₂ O-Cyclopropyl

β ·

R ¹ R ² R ³ X ¹ Y • monophosphate H H H nh ₂ SH monophosphate H H H nh ₂ SMe monophosphate H ÍH 1 H nh ₂ SEt monophosphate H H H nh ₂ S-cyclopropyl monophosphate H H H nh ₂ F monophosphate H H H nh ₂ Cl monophosphate H H H nh ₂ Br monophosphate H H H nh ₂ AND diphosphate H H H nh ₂ nh ₂ diphosphate H H H nh ₂ NH-acetyl diphosphate H H H nh ₂ NH-cyclopropyl diphosphate H H T ^T xx nh ₂ NH-methyl diphosphate H H H nh ₂ NH-ethyl diphosphate H H H nh ₂ OH diphosphate H H H nh ₂ O-acetyl diphosphate H H H nh ₂ About me diphosphate H H H nh ₂ OEt diphosphate H H H nh ₂ O-Cyclopropyl diphosphate H H H nh ₂ SH diphosphate H H H nh ₂ SMe diphosphate H H H nh ₂ SEt diphosphate H H H nh ₂ S-cyclopropyl diphosphate H H H nh ₂ F diphosphate H H H nh ₂ Cl diphosphate H H H nh ₂ Br diphosphate H H H nh ₂ AND triphosphate H H H nh ₂ nh ₂ triphosphate H H H nh ₂ NH-acetyl triphosphate H H H nh ₂ NH-cyclopropyl triphosphate H H H nh ₂ NH-methyl triphosphate H H H. nh ₂ NH-ethyl

SEW

R ¹ R ² R ³ x ¹ - X ¹ Y • triphosphate H H H nh ₂ OH triphosphate H H H nh ₂ About me triphosphate H H H nh ₂ OEt triphosphate H H H nh ₂ O-Cyclopropyl triphosphate H H H nh ₂ O-acetyl triphosphate H H H nh ₂ SH triphosphate H H H nh ₂ SMe triphosphate H H H nh ₂ SEt triphosphate H H H nh ₂ S-cyclopropyl triphosphate H H H nh ₂ F triphosphate H H H nh ₂ Cl triphosphate H H H nh ₂ Br triphosphate H H H nh ₂ AND monophosphate monophosphate monophosphate H nh ₂ nh ₂ monophosphate monophosphate monophosphate H nh ₂ NH-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ OH monophosphate monophosphate monophosphate H nh ₂ F monophosphate monophosphate monophosphate H nh ₂ Cl diphosphate diphosphate diphosphate H nh ₂ NH ₂ diphosphate diphosphate diphosphate H nh ₂ NH-cyclopropyl diphosphate diphosphate diphosphate H nh ₂ OH diphosphate diphosphate diphosphate H nh ₂ F diphosphate diphosphate diphosphate H nh ₂ Cl triphosphate triphosphate triphosphate H nh ₂ NH ₂ triphosphate triphosphate triphosphate H nh ₂ NH-cyclopropyl triphosphate triphosphate triphosphate H nh ₂ OH triphosphate triphosphate triphosphate H nh ₂ F triphosphate triphosphate triphosphate H nh ₂ Cl H H H F nh ₂ nh ₂ H H H F nh ₂ NH-cyclopropyl H H H F, nh ₂ OH

4Ζ £

R ¹ R ² R ³ T— X ² Y H ! H H F nh ₂ F H H H F nh ₂ Cl H H H Cl nh ₂ nh ₂ H H H Cl nh ₂ NH-cyclopropyl H H H Cl nh ₂ OH H H H Cl nh ₂ F H H H Cl nh ₂ Cl H H H Br nh ₂ nh ₂ H H H Br nh ₂ NH-cyclopropyl H H H Br nh ₂ OH H H H Br nh ₂ F H H H Br nh ₂ Cl H H H nh ₂ nh ₂ nh ₂ H H H nh ₂ nh ₂ NH-cyclopropyl H H H nh ₂ nh ₂ OH H H H nh ₂ nh ₂ F H H H nh ₂ nh ₂ Cl H H H SH nh ₂ nh ₂ H H H SH nh ₂ NH-cyclopropyl H H H SH nh ₂ OH H H H SH nh ₂ F H H H SH nh ₂ Cl acetyl H H H nh ₂ nh ₂ acetyl H H H nh ₂ NH-cyclopropyl acetyl H H H nh ₂ OH acetyl H H H nh ₂ F acetyl H H H nh ₂ Cl acetyl H H F nh ₂ nh ₂ acetyl H H F nh ₂ NH-cyclopropyl acetyl H H F nh ₂ OH acetyl H H F nh ₂ F

* · *

42Ψ

R ¹ R ² R * x ¹ - X ² Y acetyl H H F nh ₂ Cl H acetyl acetyl H nh ₂ nh ₂ H acetyl acetyl H nh ₂ NH-cyclopropyl H acetyl acetyl H nh ₂ OH H acetyl acetyl H nh ₂ F H acetyl acetyl H nh ₂ Cl acetyl acetyl acetyl H nh ₂ nh ₂ acetyl acetyl acetyl H nh ₂ NH-cyclopropyl acetyl acetyl acetyl H nh ₂ OH acetyl acetyl acetyl H nh ₂ F acetyl acetyl acetyl H nh ₂ Cl monophosphate acetyl acetyl H nh ₂ nh ₂ monophosphate acetyl acetyl H nh ₂ NH-cyclopropyl monophosphate acetyl acetyl H nh ₂ OH monophosphate acetyl acetyl H nh ₂ F monophosphate acetyl acetyl H nh ₂ Cl diphosphate acetyl acetyl H nh ₂ nh ₂ diphosphate acetyl acetyl H nh ₂ NH-cyclopropyl diphosphate acetyl acetyl H nh ₂ OH diphosphate acetyl acetyl H nh ₂ F diphosphate acetyl acetyl H nh ₂ Cl triphosphate acetyl acetyl H nh ₂ nh ₂ triphosphate acetyl acetyl H nh ₂ NH-cyclopropyl triphosphate acetyl acetyl H nh ₂ OH triphosphate acetyl acetyl H nh ₂ F triphosphate acetyl acetyl H nh ₂ Cl H H H H Cl H H H H H Cl H H H H H Cl nh ₂ H H H H Cl NH-cyclopropyl H H H H Cl NH-methyl

R ¹ R ² R ³ X ¹ X ² Y Η H H H Cl NH-ethyl Η H H H Cl NH-acetyl Η H H H Cl OH Η H H H Cl About me Η H H H Cl OEt Η H H H Cl O-Cyclopropyl Η H H H Cl O-acetyl Η H H H Cl SH Η H H H Cl SMe Η H H H Cl SEt Η H H H Cl S-cyclopropyl monophosphate H H H Cl nh ₂ monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H Cl NH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl O-acetyl monophosphate H H H Cl About me monophosphate H H H Cl OEt monophosphate H H H Cl O-Cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl nh ₂ diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H * ' Cl OH

· · · * * * * * * ·

9 ·· · * ······ «· ····

R ¹ R ² R ³ X ¹ X ² Y diphosphate H H H Cl O-acetyl diphosphate H H H Cl About me diphosphate H H H Cl OEt diphosphate H H H Cl O-Cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl tiiphosphate H H H Cl nh ₂ triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyciopropyl triphosphate H H H Cl NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl About me triphosphate H H H Cl OEt triphosphate H H H Cl O-Cyclopropyl triphosphate H H H Cl O-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphate H H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphate monophosphate monophosphate H Cl NH ₂ monophosphate monophosphate monophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH ₂ diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate H Cl nh ₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH

23ΰ

R ¹ R ² R ³ X ¹ X ² Y Η H H F Cl nh ₂ Η H H F Cl NH-cyclopropyl Η H H F Cl OH Η H H Cl Cl nh ₂ Η H H Cl Cl NH-cyclopropyl Η H H Cl Cl OH Η H H Br Cl NH ₂ Η H H Br Cl NH-cyclopropyl Η H H Br Cl OH Η H H nh ₂ Cl NH ₂ Η H H nh ₂ Cl NH-cyclopropyl Η H H nh ₂ Cl OH Η H H SH Cl NH ₂ Η H H SH Cl NH-cyclopropyl Η H H SH Cl OH acetyl H H H Cl NH ₂ acetyl H H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH ₂ acetyl H H F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH ₂ H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetyl acetyl H Cl NH ₂ acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetyl acetyl H Cl OH monophosphate acetyl acetyl H Cl nh ₂ monophosphate acetyl acetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H · Cl NH ₂

434

R ¹ R ² R ² x ¹ - Ι ^χ1 Y diphosphate acetyl acetyl H C1 NH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetyl acetyl H Cl nh ₂ triphosphate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H Cl OH H H H H Cl nh ₂ ^H H H H Cl NH-cyclopropyl H H H H Cl OH H H H H Br nh ₂ H H H H Br NH-cyclopropyl H H H H Br OH

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula IV can also be prepared.

(IV) where

R ¹ R ² R ^J X ¹ Y H H H H H H H H H nh ₂ H H H H NH-cyclopropyl H H H H NH-methyl H H H H * NH-ethyl H H H H NH-acetyl

• · · · · ·

R ¹ R ² R ³ X ¹ Y Η H H H OH Η H H H About me Η H H H OEt Η H H H O-Cyclopropyl Η H H H O-acetyl Η H H H SH Η H H H SMe Η H H H SEt Η H H H S-cyclopropyl monophosphate H H H nh ₂ monophosphate H H H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H O-acetyl monophosphate H H H About me monophosphate H H H OEt monophosphate H H H O-Cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate H H H S-cyclopropyl diphosphate H H H nh ₂ diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H About me

»· · · · · · · · · · · · · · · · · · · · ·

R ¹ R ² R ³ X ¹ Y diphosphate H H H OEt diphosphate H H H O-Cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H H H SEt diphosphate H H H S-cyclopropyl triphosphate H H H nh ₂ triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphate H H H About me triphosphate H H H OEt triphosphate H H H O-Cyclopropyl triphosphate H H H O-acetyl triphosphate H H H SH triphosphate H H H SMe triphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H NH ₂ diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OH triphosphate triphosphate triphosphate H nh ₂ triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F nh ₂ H H H F NH-cyclopropyl

13fy

R ¹ R ² R ³ x ¹ - Y H H H F OH H H H Cl nh ₂ H H H Cl NH-cyclopropyl H H H Cl OH H H H Br nh ₂ H H H Br NH-cyclopropyl H H H Br OH H H H nh ₂ nh ₂ H H H nh ₂ NH-cyclopropyl H H H nh ₂ OH H H H SH nh ₂ H H H SH NH-cyclopropyl H H H SH OH acetyl H H Η nh ₂ acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F nh ₂ acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H nh ₂ H acetyl acetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH ₂ acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphate acetyl acetyl H NH ₂ monophosphate acetyl acetyl H NH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH ₂ diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H * OH

R ¹ R ² R ² X ¹ Y triphosphate acetyl acetyl NH ₂ triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula VII can also be prepared.

(VU) where:

R ¹  ““ * ----- R ' R ³ R ⁶ X Base H H H ch ₃ 0 2,4-0- Diacetyluracil H H H ch ₃ 0 Hypoxanthine H H H ch ₃ 0 2,4-0- Diacetylthymine H H H ch ₃ 0 Thymine H H H ch ₃ 0 Cytosine H H H ch ₃ 0 4- (N-mono- acetyl) cytosine H H H ch ₃ 0 4- (N, N-) diacetyl) cytosine H H H ch ₃ 0 Uráčil H H H ch ₃ 0 5-Fluorouracil H H H ch ₃ with 2,4-0- Diacetyluracil H H H ch ₃ with Hypoxanthine

R ¹ R ² R ^J R ⁶ X Base Η H H CH ₃ with 2,4-0- Diacetylthymine Η H H ch ₃ with Thymine Η H H ch ₃ with Cytosine Η H H ch ₃ with 4- (N-mono- acetyl) cytosine Η H H ch ₃ with 4- (N, N-) diacetyl) cytosine Η H H ch ₃ S ' Uráčil Η H H ch ₃ with 5-Fluorouracil monophosphate H H ch ₃ 0 2,4-0- Diacetyluracil monqphosphate H H ch ₃ 0 Hypoxanthine monophosphate H H ch ₃ 0 2,4-0- Diacetylthym monophosphate H H ch ₃ 0 Thymine monophosphate H H ch ₃ 0 Cytosine monophosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ 0 Uráčil monophosphate H H ch ₃ 0 5-Fluorouracil monophosphate H H ch ₃ with 2,4-0- Diacetyluracil monophosphate H H ch ₃ with Hypoxanthine monophosphate H H ch ₃ with 2,4-0- Diacetylthym / A? monophosphate H H ch ₃ with Thymine monophosphate H H ch ₃ with Cytosine monophosphate H H ch ₃ · with 4- (N-mono- acetyl) cytosine

/ Í37-

R ¹ R ² R ³ R ⁶ X Base monophosphate H H ch ₃ with 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ with Uráčil monophosphate H H ch ₃ with 5-Fluorouracil diphosphate H H ch ₃ 0 2,4-0- Diacetyluracil diphosphate H H ch ₃ 0 Hypoxanthine diphosphate H H ch ₃ 0 2,4-0- Diacetylthymine diphosphate H H ch ₃ 0 Thymine diphosphate H H ch ₃ 0 Cytosine diphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine diphosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine diphosphate H H ch ₃ 0 Uráčil diphosphate H H ch ₃ 0 5-Fluorouracil diphosphate H H ch ₃ with 2,4-0- Diacetyluracil diphosphate H H ch ₃ with Hypoxanthine diphosphate H H ch ₃ with 2,4-0- Diacetylthymine diphosphate H H ch ₃ with Thymine diphosphate H H ch ₃ with Cytosine triphosphate H H ch ₃ 0 2,4-0- Diacetyluracil triphosphate H H ch ₃ 0 Hypoxanthine triphosphate H H ch ₃ O 2,4-0- Diacetylthymine triphosphate H H ch ₃ 0 Thymine triphosphate H H ch ₃ 0 Cytosine

· v v * «v v v v

R ¹ R ² R ³ R ⁶ X Base triphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine triphosphate H H ch ₃ O 4- (N, N-) diacetyl) cytosine triphosphate H H ch ₃ 0 Uráčil triphosphate H H ch ₃ 0 5-Fluorouracil triphosphate H H ch ₃ with 2,4-0- Diacetyluracil triphosphate H H ch ₃ with Hypoxanthine triphosphate H H ch ₃ with 2,4-0- Diacetylthymine triphosphate H H ch ₃ with Thymine triphosphate H H ch ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ O 2,4-0- Diacetyluracil monophosphate monophosphate monophosphate cf ₃ 0 Hypoxanthine monophosphate monophosphate monophosphate cf ₃ 0 2,4-0- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ 0 Thymine monophosphate monophosphate monophosphate cf ₃ 0 Cytosine monophosphate monophosphate monophosphate cf ₃ 0 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ O Uráčil monophosphate monophosphate monophosphate cf ₃ 0 5-Fluorouracil monophosphate monophosphate monophosphate cf ₃ with 2,4-0- Diacetyluracil monophosphate monophosphate monophosphate cf ₃ with Hypoxanthine monophosphate monophosphate monophosphate cf ₃ with 2,4-0- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ with Thymine

v · · * Λ k k k k k k k k k k k k k k k k k k

439

R ¹ R ² R ² R ^b X Base monophosphate monophosphate monophosphate cf ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with Uráčil monophosphate monophosphate monophosphate cf ₃ with 5-Fluorouracil acetyl acetyl acetyl cf ₃ 0 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl cf ₃ with 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl 0 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl with 4- (N, N-) diacetyl) cytosine H H H ch ₃ 0 2- (N, N-diacetyl) - guanine H H H ch ₃ 0 6-O-acetyl guanine H H H ch ₃ 0 8-fluoroguanine H H H ch ₃ 0 guanine H H H ch ₃ 0 6- (N, N-diacetyl) adenine H H H ch ₃ 0 2-Fluoroadenine H H H ch ₃ 0 8-Fluoroadenine H H H ch ₃ 0 2,8-difluoro- adenine H H H ch ₃ 0 adenine H H H ch ₃ with 2- (N, N-diacetyl) - guanine H H H ch ₃ with 6-O-acetyl guanine

© · * · · i <i i i i i i

R ¹ R ² R ³ R ⁶ X Base H H H ch ₃ with 8-fluoroguanine H H H ch ₃ with guanine H H H ch ₃ with 6- (N, N-diacetyl) adenine H H H ch ₃ with 2-Fluoroadenine H H H ch ₃ with 8-Fluoroadenine H H H ch ₃ with 2,8-difluoro- adenine H H H ch ₃ with adenine monophosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine monophosphate H H ch ₃ 0 6-O-acetyl guanine monophosphate H H ch ₃ 0 8-fluoroguanine monophosphate H H ch ₃ 0 guanine monophosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine ! monophosphate H H ch ₃ 0 2-Fluoroadenine monophosphate H H ch ₃ 0 8-Fluoroadenine monophosphate H H ch ₃ 0 2,8-difluoro- adenine monophosphate H H ch ₃ 0 adenine monophosphate H H ch ₃ with 2- (N, N-diacetyl) - guanine monophosphate H H CHj with 6-O-acetyl guanine monophosphate H H ch ₃ with 8-fluoroguanine monophosphate H H ch ₃ with guanine monophosphate H H ch ₃ with 6- (N, N-diacetyl) adenine monophosphate H H ch ₃ . with 2-Fluoroadenine monophosphate H H ch ₃ with 8-Fluoroadenine

• O O O O O O - - - - - - ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ··· »·

R ¹ R ² R ³ R ^<> X Base monophosphate H H ch ₃ with 2,8-difluoro- adenine monophosphate H H ch ₃ with adenine diphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine diphosphate H H ch ₃ 0 6-O-acetyl guanine diphosphate H H ch ₃ 0 8-fluoroguanine diphosphate H H ch ₃ 0 guanine diphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ 0 2-Fluoroadenine diphosphate H H ch ₃ 0 8-Fluoroadenine diphosphate H H ch ₃ 0 2,8-difluoro- adenine diphosphate H H ch ₃ 0 adenine diphosphate H H ch ₃ with 2- (N, N-diacetyl) - guanine diphosphate H H ch ₃ with 6-O-acetyl guanine diphosphate H H ch ₃ with 8-fluoroguanine diphosphate H H ch ₃ with guanine diphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ with 2-Fluoroadenine diphosphate H H CHj with 8-Fluoroadenine diphosphate H H ch ₃ with 2,8-difluoro- adenine diphosphate H H ch ₃ with adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine

• * · ·

4½

R ¹ R ² R ³ R ^b X Base triphosphate H H ch ₃ 0 6-O-acetyl guanine triphosphate H H ch ₃ 0 8-fluoroguanine triphosphate H H ch ₃ 0 guanine triphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ 0 2-Fluoroadenine triphosphate H H ch ₃ 0 8-Fluoroadenine triphosphate H H ch ₃ 0 2,8-difluoro- adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine triphosphate H H ch ₃ with 6-O-acetyl guanine triphosphate H H. ch ₃ with 8-fhioroguanine triphosphate and H H ch ₃ with guanine triphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ with 2-Fluoroadenine triphosphate H H ch ₃ with 8-Fluoroadenine triphosphate H H ch ₃ with 2,8-difluoro- adenine triphosphate H H ch ₃ with adenine monophosphate monophosphate monophosphate cf ₃ 0 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ 0 6-O-acetyl guanine monophosphate monophosphate monophosphate J cf ₃ 0 8-Fluoro guanine monophosphate monophosphate monophosphate cf ₃ 0 guanine monophosphate monophosphate monophosphate cf ₃ 0 6- (N, N-diacetyl) adenine monophosphate monophosphate monophosphate cf ₃ 0 2-Fluoroadenine

M3

R ¹ R ² R ³ R ’ X Base monophosphate monophosphate monophosphate cf ₃ 0 8-Fluoroadenine monophosphate monophosphate monophosphate CF ₃ 0 2,8-difluoro- adenine monophosphate monopho sphate monophosphate cf ₃ 0 adenine monophosphate monophosphate monophosphate cf ₃ with 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ with 6-O-acetyl guanine monophosphate monophosphate monophosphate cf ₃ with 8-fhioroguanine monophosphate monophosphate monophosphate cf ₃ with guanine monophosphate monophosphate monophosphate cf ₃ with 6- (N, N-diacetyl) adenine monophosphate monophosphate monophosphate cf ₃ with 2-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 8-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 2,8-difiuoro- adenine monophosphate monophosphate monophosphate cf ₃ with adenine acetyl acetyl acetyl cf ₃ 0 guanine acetyl acetyl acetyl j cf ₃ with guanine acetyl acetyl acetyl | and t and 2-bromo- vinyl 0 guanine acetyl acetyl acetyl j 2-bromo- vinyl with guanine

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula VIII can also be prepared.

• • •

kd &:

R ¹ R ² R ^é X | Base H H ch ₃ 0 2,4-O-Diacetyluracil H H ch ₃ 0 1 Hypoxanthine H H ch ₃ 0 2,4-O-Diacetylthymine H H ch ₃ 0 Thymine H H ch ₃ 0 Cytosine H H ch ₃ 0 4- (N-mono-acetyl) cytosine H H ch ₃ 0 4- (N, N-diacetyl) cytosine H H ch ₃ 0 Uráčil H H ch ₃ 0 5-Fluorouracil H H ch ₃ with 2,4-O-Diacetyluracil H H ch ₃ with Hypoxanthine H H ch ₃ with 2,4-O-Diacetylthymine H H ch ₃ with Thymine H H ch ₃ with Cytosine H H ch ₃ with 4- (N-mono-acetyl) cytosine H H ch ₃ with 4- (N, N-diacetyl) cytosine H H ch ₃ with Uráčil H H ch ₃ with 5-Fluorouracil monophosphate H ch ₃ 0 2,4-O-Diacetyluracil monophosphate H ch ₃ 0 Hypoxanthine monophosphate H ch ₃ 0 2,4-O-Diacetylthymine monophosphate H ch ₃ 0 Thymine monophosphate H ch ₃ 0 Cytosine monophosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine monophosphate H ch ₃ 0 4- (N, N-diacetyl) cytosine monophosphate H ch ₃ 0 Uráčil monophosphate H ch ₃ 0 5-Fluorouracil monophosphate H ch ₃ with 2,4-O-Diacetyluracil monophosphate H ch ₃ with Hypoxanthine monophosphate H čh ₃ with 2,4-O-Diacetylthymine

• · · ► · · · · · · · · · · ·

R ¹ R ² R ⁶ X Base monophosphate H CH ₃ with Thymine monophosphate H ch ₃ with Cytosine monophosphate H ch ₃ with 4- (N-mono-acetyl) cytosine monophosphate H ch ₃ with 4- (N, N-diacetyl) cytosine monophosphate H ch ₃ with Uráčil monophosphate H ch ₃ with 5-Fluorouracil diphosphate H ch ₃ 0 2,4-O-Diacetyluracil diphosphate H ch ₃ 0 Hypoxanthine diphosphate H ch ₃ 0 2,4-O-Diacetylthymine diphosphate H ch ₃ 0 Thymine diphosphate H ch ₃ 0 Cytosine diphosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine diphosphate H ch ₃ 0 4- (N, N-diacetyl) cytosine diphosphate H ch ₃ 0 Uráčil diphosphate H ch ₃ 0 5-Fluorouracil diphosphate H ch ₃ with 2,4-O-Diacetyluracil diphosphate H ch ₃ with Hypoxanthine diphosphate H ch ₃ with 2,4-O-Diacetylthymine diphosphate H ch ₃ with Thymine diphosphate H ch ₃ with Cytosine diphosphate H ch ₃ with 4- (N-mono-acetyl) cytosine diphosphate H ch ₃ with 4- (N, N-diacetyl) cytosine diphosphate H ch ₃ with Uráčil diphosphate H čh ₃ with 5-Fluorouracil triphosphate H ch ₃ 0 2,4-O-Diacetyluracil triphosphate H ch ₃ 0 Hypoxanthine triphosphate H ch ₃ 0 2,4-O-diacetylthymine triphosphate H ch ₃ 0 Thymine triphosphate H ch ₃ 0. Cytosine triphosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine triphosphate H ch ₃ 0 4- (N ', N-diacetyl) cytosine

ΊΜ>

R ¹ R ² R ‘ X Base triphosphate H ch ₃ 0 Uráčil triphosphate H ch ₃ 0 5-Fluorouracil triphosphate H ch ₃ with 2,4-O-Diacetyluracil triphosphate H ch ₃ with Hypoxanthine triphosphate H ch ₃ with 2,4-O-Diacetylthymine triphosphate H ch ₃ with Thymine triphosphate H ch ₃ with Cytosine triphosphate H ch ₃ with 4- (N-mono-acetyl) cytosine triphosphate H ch ₃ with 4- (N, N-diacetyl) cytosine triphosphate H ch ₃ with Uráčil triphosphate H ch ₃ with 5-Fluorouracil monophosphate monophosphate cf ₃ 0 2,4-O-Diacetyluracil monophosphate monophosphate cf ₃ 0 Hypoxanthine monophosphate monophosphate cf ₃ 0 2,4-O-Diacetylthymine monophosphate monophosphate cf ₃ 0 Thymine monophosphate monophosphate cf ₃ 0 Cytosine monophosphate monophosphate cf ₃ 0 4- (N-mono-acetyl) cytosine monophosphate monophosphate cf ₃ 0 4- (N, N-diacetyl) cytosine monophosphate monophosphate cf ₃ 0 Uráčil monophosphate monophosphate cf ₃ 0 5-Fluorouracil monophosphate monophosphate cf ₃ with 2,4-O-Diacetyluracil monophosphate monophosphate cf ₃ with Hypoxanthine monophosphate monophosphate cf ₃ with 2,4-O-Diacetylthymine monophosphate monophosphate cf ₃ with Thymine monophosphate monophosphate cf ₃ with Cytosine monophosphate monophosphate cf ₃ with 4- (N-mono-acetyl) cytosine monophosphate monophosphat.e cf ₃ with 4- (N, N-diacetyl) cytosine monophosphate monophosphate cf ₃ with Uráčil monophosphate monophosphate cf ₃ with 5-Fluorouracil acetyl acetyl cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl acetyl cf ₃ with 4- (N, N-diacetyl) cytosine

R ¹ R ² R ⁶ X Base acetyl acetyl 2-bromo- vinyl 0 4- (N, N-diacetyl) cytosine acetyl acetyl 2-bromo- vinyl with 4- (N, N-diacetyl) cytosine H H ch ₃ 0 2- (N, N-diacetyl) guanine H H ch ₃ 0 6-O-acetyl guanine H H ch ₃ 0 8-fluoroguanine H H ch ₃ 0 guanine H H ch ₃ 0 6- (N, N-diacetyl) adenine H H ch ₃ 0 2-Fluoroadenine H H ch ₃ 0 8-Fluoroadenine H H ch ₃ 0 2,8-difluoro-adenine H H ch ₃ 0 adenine H H ch ₃ with 2- (N, N-diacetyl) guanine H H ch ₃ with 6-O-acetyl guanine H H ch ₃ with 8-fluoroguanine H H ch ₃ with guanine H H ch ₃ with 6- (N, N-diacetyl) adenine H H ch ₃ with 2-Fluoroadenine H H ch ₃ with 8-Fluoroadenine H H ch ₃ with 2,8-difluoro-adenine H H ch ₃ with adenine monophosphate H ch ₃ 0 2- (N, N-diacetyl) guanine monophosphate H ch ₃ 0 6-O-acetyl guanine monophosphate H ch ₃ 0 8-fluoroguanine monophosphate H ch ₃ 0 guanine monophosphate H ch ₃ 0 6- (N, N-diacetyl) adenine monophosphate H ch ₃ 0 2-Fluoroadenine monophosphate H ch ₃ 0 8-Fluoroadenine monophosphate H ch ₃ 0 2,8-difluoro-adenine monophosphate H ch ₃ 0 1 adenine

• · · · · · · · ·

R ¹ R ² R ⁶ X Base monophosphate H C% with 2- (N, N-diacetyl) guanine monophosphate H ch ₃ with 6-O-acetyl guanine monophosphate H ch ₃ with 8-fluoroguanine monophosphate H ch ₃ with guanine monophosphate H ch ₃ with 6- (N, N-diacetyl) adenine monophosphate H ch ₃ with 2-Fluoroadenine monophosphate H ch ₃ with 8-Fluoroadenine monophosphate H ch ₃ with 2,8-difluoro-adenine monophosphate H ch ₃ with adenine diphosphate H ch ₃ 0 2- (N ' _, N'-diacetyl) guanine diphosphate H ch ₃ 0 6-O-acetyl guanine diphosphate H ch ₃ 0 8-fluoroguanine diphosphate H ch ₃ 0 guanine diphosphate H ch ₃ 0 6- (N, N-diacetyl) adenine diphosphate H ch ₃ 0 2-Fluoroadenine diphosphate H ch ₃ 0 8-Fluoroadenine diphosphate H ch ₃ 0 2,8-difluoro-adenine diphosphate H ch ₃ 0 adenine diphosphate H ch ₃ with 2- (N, N-diacetyl) guanine diphosphate H ch ₃ with 6-O-acetyl guanine diphosphate H ch ₃ with 8-fluoroguanine diphosphate H ch ₃ with guanine diphosphate H ch ₃ with 6- (N, N-diacetyl) adenine diphosphate H ch ₃ with 2-Fluoroadenine diphosphate H ch ₃ with 8-Fluoroadenine diphosphate H ch ₃ with 2,8-difluoro-adenine diphosphate H ch ₃ with adenine triphosphate H ch ₃ 0 2- (N, N-diacetyl) guanine triphosphate H ch ₃ 0 6-O-acetyl guanine triphosphate H ch ₃ 0 8-fluoroguanine triphosphate H ch ₃ 0 guanine

• · · ·

R ¹ R ² R ⁶ X Base triphosphate H ch ₃ 0 6- (N, N-acetyl) -adenine triphosphate H ch ₃ 0 2-Fluoroadenine triphosphate H ch ₃ 0 8-Fluoroadenine triphosphate H ch ₃ 0 2,8-difluoro-adenine triphosphate H ch ₃ 0 adenine triphosphate H ch ₃ with 2- (N, N-diacetyl) guanine triphosphate H ch ₃ with 6-O-acetyl guanine triphosphate H ch ₃ with 8-fluoroguanine triphosphate H ch ₃ with guanine triphosphate H ch ₃ with 6- (N, N-diacetyl) adenine triphosphate H ch ₃ with 2-Fluoroadenine triphosphate H ch ₃ with 8-Fluoroadenine triphosphate H ch ₃ with 2,8-difluoro-adenine triphosphate H ch ₃ with adenine monophosphate monophosphate cf ₃ 0 2- (N, N-diacetyl) guanine monophosphate monophosphate cf ₃ 0 6-O-acetyl guanine monophosphate monophosphate cf ₃ 0 8-fluoroguanine monophosphate monophosphate cf ₃ 0 guanine monophosphate monophosphate cf ₃ 0 6- (N, N-diacetyl) adenine monophosphate monophosphate cf ₃ 0 2-Fluoroadenine monophosphate monophosphate cf ₃ 0 8-Fluoroadenine monophosphate monophosphate cf ₃ 0 2,8-difluoro-adenine monophosphate monophosphate cf ₃ 0 adenine monophosphate monophosphate cf ₃ with 2- (N, N-diacetyl) guanine monophosphate monophosphate cf ₃ with 6-O-acetyl guanine monophosphate monophosphate cf ₃ with 8-fluoroguanine monophosphate monophosphate cf ₃ with guanine monophosphate monophosphate cf ₃ with 6- (N, N-diacetyl) adenine monophosphate monophosphate cf ₃ with 2-Fluoroadenine monophosphate monophosphate cf ₃ with 8-Fluoroadenine monophosphate monophosphate cf ₃ with 2,8-difluoro-adenine

V50

R ¹ R ² R ⁴ X Base monophosphate monophosphate cf ₃ with adenine acetyl acetyl cf ₃ 0 gnanřne acetyl acetyl cf ₃ with gnanine acetyl acetyl 2-bromo- vinyl 0 guanine acetyl acetyl 2-bromo- vinyl with guanine

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula IX can also be prepared.

Base (IX) kc / phi:

R ¹ R ⁴ X Base H ch ₃ 0 2,4-O-Diacstyluracil H ch ₃ 0 Kypoxantbine H ch ₃ 0 2.4-O-Diacetylthymine H ch ₃ 0 Thymine H ch ₃ 0 Cytosine H ch ₃ 0 4- (N-mono-acetyl) cytosme H ch ₃ 0 4- (N, N-diacetyl) cytosine H ch ₃ 0 Uráčil H ch ₃ 0 5-Fluorouracil H ch ₃ with 2,4-0'Diacetyluracil H ch ₃ with Hypoxanthine H ch ₃ 0 ^sec 2,4-O-Diacetylthymine

• ·

R ¹ R ⁶ X Base H ch ₃ with Thymine H ch ₃ with Cytosine H ch ₃ with 4- (N-mono-acetyl) cytosine H ch ₃ with 4- (N, N-diacetyl) cytosine H ch ₃ with Uráčil H ch ₃ with 5-Fluorouracil monophosphate ch ₃ 0 2,4-O-Diacetyluracil monophosphate ch ₃ 0 Hypoxanthine monophosphate ch ₃ 0 2,4-O-Diacetylthymine monophosphate ch ₃ 0 Thymine monophosphate ch ₃ 0 Cytosine monophosphate ch ₃ 0 4- (N-mono-acetyl) cytosine monophosphate ch ₃ 0 4- (N, N-diacetyl) cytosine monophosphate ch ₃ 0 Uráčil monophosphate ch ₃ 0 5-Fluorouracil monophosphate ch ₃ with 2,4-O-Diacetyluracil monophosphate ch ₃ with Hypoxanthine monophosphate ch ₃ with 2,4-O-Diacetylthymine monophosphate ch ₃ with Thymine monophosphate ch ₃ with Cytosine monophosphate ch ₃ with 4- (N-mono-acetyl) cytosine monophosphate ch ₃ with 4- (N, N-diacetyl) cytos monophosphate ch ₃ with Uráčil monophosphate ch ₃ with 5-Fluorouracil diphosphate ch ₃ 0 2,4-O-Diacetyluracil diphosphate ch ₃ 0 Hypoxanthine diphosphate ch ₃ 0 2,4-O-Diacetylthymine diphosphate ch ₃ 0 Thymine diphosphate ch ₃ 0 Cytosine diphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine diphosphate ch ₃ 0 4- (N, N-diacetyl) cytosine

451-

R ¹ R ⁶ X Base diphosphate ch ₃ 0 Uráčil diphosphate ch ₃ 0 5-Fluorouracil diphosphate ch ₃ with 2,4-O-Diacetyluracil diphosphate ch ₃ with Hypoxanthine diphosphate ch ₃ with 2,4-O-Diacetylthymine diphosphate ch ₃ with Thymine diphosphate ch ₃ with Cytosine triphosphate ch ₃ 0 2,4-O-Diacetyluracil triphosphate ch ₃ 0 Hypoxanthine triphosphate ch ₃ 0 2,4-O-Diacetylthymine triphosphate ch ₃ 0 Thymine triphosphate ch ₃ 0 Cytosine triphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine triphosphate ch ₃ 0 4- (N, N-diacetyl) cytosine triphosphate ch ₃ 0 Uráčil triphosphate ch ₃ 0 5-Fluorouiacil triphosphate ch ₃ with 2,4-O-Diacetyluracil triphosphate ch ₃ with Hypoxanthine triphospahate ch ₃ with 2,4-O-Diacetylthymine triphospahate ch ₃ with Thymine triphospahate ch ₃ with Cytosine monophosphate cf ₃ 0 2,4-O-Diacetyluracil monophosphate cf ₃ 0 Hypoxanthine monophosphate cf ₃ 0 2,4-O'Diacetylthymine monophosphate cf ₃ 0 1 Thymine monophosphate cf ₃ 0 Cytosine monophosphate cf ₃ 0 4- (N-mono-acetyl) cytosine monophosphate cf ₃ 0 4- (N, N-diacetyl) cytos monophosphate cf ₃ 0 Uráčil monophosphate cf ₃ 0 5-Fluorouracil monophosphate cf ₃ with 2,4-O-Diacetyluracil

R ¹ R ⁶ X Base monophosphate cf ₃ with Hypoxanthine monophosphate cf ₃ with 2,4-O-Diacetylthymine monophosphate cf ₃ with Thymine monophosphate cf ₃ · with Cytosine monophosphate cf ₃ with 4- (N-mono-acetyl) cytosine monophosphate cf ₃ with 4- (N, N-diacetyl) cytosine monophosphate cf ₃ with Uráčil monophosphate cf ₃ with 5-Fluorouracil acetyl cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl cf ₃ with 4- (N, N-diacetyl) cytosine acetyl 2-bromo-vinyl 0 4- (N, N-diacetyl) cytosine acetyl 2-bromo-vinyl with 4- (N, N-diacetyl) cytosine -

Nucleosides of formula XVI can also be prepared using appropriate sugars and pyrimidine or purine bases.

Base

R ¹⁰ _χ R ^{8 9} R ⁷ (XVI) where:

R ¹ R " R ' R ⁸ X Base R ¹⁰ R ⁹ H ch ₃ H H 0 2,4-O-Diacetyluracil OH Me H ch ₃ H H 0 Hypoxanthine OH Me H ch ₃ H H 0 2,4-O-Diacetylthymine OH Me H ch ₃ H H 0 Thymine OH Me H ch ₃ H H 0 Cytosine OH Me H ch ₃ H H 0 4- (N-mono-acetyl) cytosine OH Me H ch ₃ H H 0 4- (N, N-diacetyl) cytosine OH Me

R ¹ R ⁶ R ⁷ R ⁸ X Base R ^lů ΊΡ H ch ₃ H H 0 Uráčil OH Me H ch ₃ H H 0 J 5-Fluorouracil OH Me H ch ₃ H H with 2,4-O-Diacetyluracil OH Me H ch ₃ H H with Hypoxanthine OH Me H ch ₃ H H with 2,4-O-Diacetylthymine OH Me H ch ₃ H H with Thymine OH Me H ch ₃ H H with Cytosine OH Me H ch ₃ H H with 4- (N-mono-acetyl) cytosine OH Me H ch ₃ H H with 4- (N, N-diacetyl) cytosine OH Me H ch ₃ H H with Uráčil OH Me H ch ₃ H H with 5-Fluorouracil OH Me monophosphate ch ₃ H H 0 2,4-O-Diacetyluracil OH Me monophosphate ch ₃ H H 0 Hypoxanthine OH Me monophosphate ch ₃ H H 0 2,4-O-Diacetylthymine OH Me monophosphate ch ₃ H H 0 Thymine OH Me monophosphate ch ₃ H H 0 Cytosine OH Me monophosphate ch ₃ H H 0 4- (N-mono-acetyl) cytosine OH Me monophosphate ch ₃ H H 0 4- (N, N-diacetyl) cytosine OH Me monophosphate ch ₃ H H 0 Uráčil OH Me monophosphate ch ₃ H H 0 5-Fluorouracil OH Me monophosphate ch ₃ H H with 2,4-O-Diacetyluracil OH Me monophosphate ch ₃ H H with Hypoxanthine OH Me monophosphate ch ₃ H H with 2,4-O-Diacetylthymine OH Me monophosphate ch ₃ H H with Thymine OH Me monophosphate ch ₃ H H with Cytosine OH Me monophosphate ch ₃ H H with 4- (N-mono-acetyl) cytosine OH Me monophosphate ch ₃ H H with 4- (N, N-diacetyl) cytosine OH Me monophosphate ch ₃ H H with Uráčil OH Me monophosphate ch ₃ H H with 5-Fluorouracil OH Me diphosphate ch ₃ H H 0 2,4-O-Diacetyluracil OH Me diphosphate ch ₃ H H 0 Hypoxanthine OH Me

• · · «

R ¹ R ⁶ 1 ^R? R * X Base R ¹⁰ ” R ^s diphosphate CH ₃ H H 0 2,4-O-Diacetylthymine OH Me diphosphate CH ₃ H H 0 Thymine OH Me diphosphate ch ₃ H H 0 Cytosine OH Me diphosphate ch ₃ H H 0 4- (N-mono-acetyl) cytosine OH Me diphosphate ch ₃ H H 0 4- (N, N-diacetyl) cytosine OH Me diphosphate ch ₃ H H 0 Uráčil OH Me diphosphate ch ₃ H H 0 5-Fluorouracil OH Me diphosphate ch ₃ H H with 2,4-O-Diacetyluracil OH Me diphosphate ch ₃ H H with Hypoxanthine OH Me diphosphate ch ₃ H H with 2,4-O-Diacetylthymine OH Me diphosphate ch ₃ H H with Thymine OH Me diphosphate ch ₃ H H with Cytosine OH Me triphosphate ch ₃ H H 0 2,4-O-Diacetyluracil OH Me triphosphate ch ₃ H H 0 Hypoxanthine OH Me triphosphate ch ₃ H H 0 2,4-O-Diacetylthymine OH Me triphosphate ch ₃ H H 0 Thymine OH Me triphosphate ch ₃ H H 0 Cytosine OH Me triphosphate ch ₃ H H 0 4- (N-mono-acetyl) cytosine OH Me triphosphate ch ₃ H H O 4- (N 1 -diacetyl) cytosme OH Me triphosphate ch ₃ H H 0 Uráčil OH Me triphosphate ch ₃ H H 0 5-Fluorouracil OH Me triphosphate ch ₃ H H with 2,4-O-Diacetyluracil OH Me triphosphate ch ₃ H H with Hypoxanthine OH Me triphosphate ch ₃ H H with 2,4-O-Diacetylthymine OH Me triphosphate ch ₃ H H with Thymine OH Me triphosphate ch ₃ H H with Cytosine OH Me monophosphate cf ₃ H H 0 2,4-O-Diacetyluracil OH Me monophosphate cf ₃ H H 0 Hypoxanthine OH Me monophosphate cf ₃ H H 0 2,4-O-Diacetylthymine OH Me monophosphate cf ₃ H H 0 Thymine OH Me monophosphate cf ₃ H H 0 Cytosine OH Me

4 4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 ···

R ¹ R ⁶ R ⁷ R ^a X Base R ¹⁰ R ⁹ monophosphate CF ₃ H H 0 4- (N-mono-acetyl) cytosine OH Me monophosphate cf ₃ H H 0 4- (N, N-diacetyl) cytosine OH Me monophosphate cf ₃ H H 0 Uráčil OH Me monophosphate cf ₃ H H 0 5-Fluorouracil OH Me monophosphate cf ₃ H H with 2,4-O-Diacetyluracil OH Me monophosphate cf ₃ H H with Hypoxanthine OH Me monophosphate cf ₃ H H with 2,4-O-Diacetylthymine OH Me monophosphate cf ₃ H H with Thymine OH Me monophosphate cf ₃ H H with Cytosine OH Me monophosphate cf ₃ H H with 4- (N-mono-acetyl) cytosine OH Me monophosphate cf ₃ H H with 4- (N, N-diacetyl) cytosine OH Me monophosphate cf ₃ H H with Uráčil OH Me monophosphate cf ₃ H H with 5-Fluorouracil OH Me acetyl ch ₃ H H 0 4- (N, N-diacetyl) cytosine H Br acetyl ch ₃ H H with 4- (N, N-diacetyl) cytosine H Br acetyl ch ₃ OH H O 4- (N, N-diacetyl) cytosine H Br acetyl ch ₃ OH H with 4- (N, N-diacetyl) cytosine H Br

Example 2. Preparation of 2'-C-methylriboadenine

The compound was prepared according to R. E.

Harry-O'kuru et al., J. Org. Chem. 1997, 62, 1754-1759, Scheme 8.

Scheme 8

BzOBzO OH

R = CH ₃

BzO

OH OH frfrfrfr frfr 4 fr

/] &

(a) Dess-Martin periodate, (b) MeMgBr / TiCl ₄ , (c) BzCl, DMAP, Et ₃ N ,. (d) bis (trimethylsilyl) acetamide, N 0 -benzoyladenine, TMSOTf, (e) NH ₃ / MeOH.

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula II can also be prepared.

R ¹ R ² R ³ iX ¹ X ² Y H H H H H H H H H H H nh ₂ H H H H H NH-cyclopropyl H H H H H NH-methyl H H H H H NH-e + yl H H H H H NH-acetyl H H H H H OH H H H H H About me H H H H H OEt H H H H H O-Cyclopropyl H H H H H O-acetyl H H H H H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F H H H H H Cl

R ¹ R ² R ³ X ¹ X ² Y H H H H H Br H H H H H AND monophosphate H H H H nh ₂ monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl monophosphate H H H H NH-methyl monophosphate H H H H NH-e + yl monophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate H H H H About me monophosphate H H H H OEt monophosphate H H H H O-Cyclopropyl monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H S-cyclopropyl monophosphate H H H H F monophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H H AND diphosphate H H H H NH ₂ diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphate H H H H About me diphosphate H H H H OEt diphosphate H H H H O-Cyclopropyl diphosphate H H H H SH

** »t t t t a a a a a a

R ¹ R ² R ²  χΐ- X ³ Y diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H H Cl diphosphate H H H H Br diphosphate H H H H AND triphosphate H H H H nh ₂ triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H About me triphosphate H H H H OEt triphosphate H H H H O-Cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H H SEt triphosphate H H H H S-cyclopropyl triphosphate H H H H F triphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H AND monophosphate monophosphate monophosphate H H nh ₂ monophosphate monophosphate monophosphate H H NH-cyclopropyl monophosphate monophosphate monophosphate H H OH monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H · H NH ₂

4 © · ©  »» * · • · * • · · © »» «© • • · • · ' • * • «· Λ » « • • • fc © · • ·· ·· C © »· © · © ·

Ί £ 0

R ¹ R ² R ³ x ¹ - x ² - Y diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H nh ₂ triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F H nh ₂ H H H F H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H nh ₂ H H H Cl H NH-cyclopropyl H H H Cl H OH H H · H Cl H F H H H Cl H Cl H H H Br H nh ₂ H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br H Cl H H H nh ₂ H nh ₂ H H H nh ₂ H NH-cyclopropyl H H H nh ₂ H OH H H H nh ₂ H F H H H nh ₂ H Cl H H H SH H nh ₂ H H H SH ’ H NH-cyclopropyl

R ¹ R ² R ³ x ¹ - X ² Y H H H SH H OH H H H SH H F H H H SH H Cl acetyl H H H H nh ₂ acetyl H H H H NH-cyclopropyl acetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H nh ₂ acetyl H H F H NH-cyclopropyl acetyl H H F H OH acetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H NH ₂ H acetyl acetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetyl acetyl acetyl H H nh ₂ acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H H OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H H Cl monophosphate acetyl acetyl H H nh ₂ monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetyl acetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetyl acetyl H H nh ₂ diphosphate acetyl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH

• · · · · • · · · • · • · • · · · · · • · · · · • · · * • · · »

4GL

R ¹ R ² R ³ X ¹ X ² Y diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H nh ₂ triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H nh ₂ H H H H H nh ₂ NH ₂ H H H H nh ₂ NH-cyclopropyl H H H H nh ₂ NH-methyl H H H H nh ₂ NH-ethyl H H H H nh ₂ NH-acetyl H H H H nh ₂ OH H H H H nh ₂ About me H H H H nh ₂ OEt H H H H nh ₂ O-Cyclopropyl H H H H nh ₂ O-acetyl H H H H nh ₂ SH H H H H nh ₂ SMe H H H H nh ₂ SEt H H H H nh ₂ S-cyclopropyl H H H H nh ₂ F H H H H nh ₂ Cl H H H H nh ₂ Br H H H H nh ₂ AND monophosphate H H H nh ₂ nh ₂ monophosphate H H H nh ₂ NH-acetyl monophosphate H H H nh ₂ NH-cyclopropyl monophosphate H H H nh ₂ NH-methyl monophosphate H H H nh ₂ NH-ethyl

• ·· · ············

R ¹ R ² R ³ 'x ¹ - X ² Y monophosphate H H H nh ₂ OH monophosphate H H H nh ₂ O-acetyl monophosphate H H H nh ₂ About me monophosphate H H H nh ₂ OEt monophosphate H H H nh ₂ O-Cyclopropyl monophosphate H H H nh ₂ SH monophosphate H H H nh ₂ SMe monophosphate H H H nh ₂ SEt monophosphate H H H nh ₂ S-cyclopropyl monophosphate H H H nh ₂ F monophosphate H H H nh ₂ Cl monophosphate H H H nh ₂ Br monophosphate H H H nh ₂ AND diphosphate H H H nh ₂ nh ₂ diphosphate H H H nh ₂ NH-acetyl diphosphate H H H nh ₂ NH-cyclopropyl diphosphate H H H nh ₂ NH-methyl diphosphate H H H nh ₂ NH-ethyl diphosphate H H H nh ₂ OH diphosphate H H H nh ₂ O-acetyl diphosphate H H H nh ₂ About me diphosphate H H H nh ₂ OEt diphosphate H H H nh ₂ O-Cyclopropyl diphosphate H H H νή ₂ SH diphosphate H H H nh ₂ SMe diphosphate H H H nh ₂ SEt diphosphate H H H nh ₂ S-cyclopropyl diphosphate H H H nh ₂ F diphosphate H H H nh ₂ Cl diphosphate H H H nh ₂ Br diphosphate H H H * nh ₂ AND

__

R ¹ R ² R ³ X ¹ X ^J Y triphosphate H H H nh ₂ nh ₂ triphosphate H H H nh ₂ NH-acetyl triphosphate H H H nh ₂ NH-cyclopropyl triphosphate H H H nh ₂ NH-methyl triphosphate H H H nh ₂ NH-ethyl triphosphate H H H nh ₂ OH triphosphate H H H nh ₂ About me triphosphate H H H nh ₂ OEt triphosphate H H H nh ₂ O-Cyclopropyl triphosphate H H H nh ₂ O-acetyl triphosphate H H H nh ₂ SH triphosphate H H H nh ₂ SMe triphosphate H H H nh ₂ SEt triphosphate H H H nh ₂ S-cyclopropyl triphosphate H H H nh ₂ F triphosphate H H H nh ₂ · Cl triphosphate H H H nh ₂ Br triphosphate H H H nh ₂ AND monophosphate monophosphate monophosphate H NH ₂ nh ₂ monophosphate monophosphate monophosphate H nh ₂ NH-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ OH monophosphate monophosphate monophosphate H nh ₂ F monophosphate monophosphate monophosphate H nh ₂ Cl diphosphate diphosphate diphosphate H nh ₂ NH ₂ diphosphate diphosphate diphosphate H nh ₂ NH-cyclopropyl diphosphate diphosphate diphosphate H nh ₂ OH diphosphate diphosphate diphosphate H nh ₂ F diphosphate diphosphate diphosphate H nh ₂ Cl triphosphate triphosphate triphosphate H nh ₂ nh ₂ triphosphate triphosphate triphosphate H nh ₂ NH-cyclopropyl triphosphate triphosphate triphosphate H nh ₂ OH

R ¹ R ² R ³ AND?- X ² Y triphosphate triphosphate triphosphate H nh ₂ F triphosphate triphosphate triphosphate H nh ₂ Cl H H H F nh ₂ nh ₂ H H H F nh ₂ NH-cyclopropyl H H H F nh ₂ OH H H H F nh ₂ F H H H F nh ₂ Cl H H H Cl nh ₂ nh ₂ H H H Cl nh ₂ NH-cyclopropyl H H H Cl nh ₂ OH H H H Cl nh ₂ F H H H Cl nh ₂ Cl H H H Br nh ₂ nh ₂ H H H Br nh ₂ NH-cyclopropyl H H H Br nh ₂ OH H H H Br nh ₂ F H H H Br nh ₂ Cl H H H nh ₂ nh ₂ nh ₂ H H H nh ₂ nh ₂ NH-cyclopropyl H H H nh ₂ nh ₂ OH H H H nh ₂ nh ₂ F H H H nh ₂ nh ₂ Cl H H H SH nh ₂ nh ₂ H H H SH nh ₂ NH-cyclopropyl H H H SH nh ₂ OH H H H SH nh ₂ F H H H SH nh ₂ Cl acetyl H H H nh ₂ nh ₂ acetyl H H H nh ₂ NH-cyclopropyl acetyl H H H nh ₂ OH acetyl H H H ** nh ₂ F

4CG

R ¹ R ² R ³ 'X ¹ X ² Y acetyl H H H nh ₂ Cl acetyl H H F nh ₂ nh ₂ acetyl H H F nh ₂ NH-cyclopropyl acetyl H H F nh ₂ OH acetyl H H F nh ₂ F acetyl H H F nh ₂ Cl H acetyl acetyl H nh ₂ nh ₂ H acetyl acetyl H nh ₂ NH-cyclopropyl H acetyl acetyl H nh ₂ OH H acetyl acetyl H nh ₂ F H acetyl acetyl H nh ₂ Cl · acetyl acetyl acetyl H nh ₂ nh ₂ acetyl acetyl acetyl H nh ₂ NH-cyclopropyl acetyl acetyl acetyl H nh ₂ OH acetyl acetyl acetyl H nh ₂ F acetyl acetyl acetyl H nh ₂ Cl monophosphate acetyl acetyl H nh ₂ NH ₂ monophosphate acetyl acetyl H nh ₂ NH-cyclopropyl monophosphate acetyl acetyl H nh ₂ OH monophosphate acetyl acetyl H nh ₂ F monophosphate acetyl acetyl H nh ₂ Cl diphosphate acetyl acetyl H nh ₂ NH ₂ diphosphate acetyl acetyl H nh ₂ NH-cyclopropyl diphosphate acetyl acetyl H nh ₂ OH diphosphate acetyl acetyl H nh ₂ F diphosphate acetyl acetyl H nh ₂ Cl triphosphate acetyl acetyl H nh ₂ nh ₂ triphosphate acetyl acetyl H nh ₂ NH-cyclopropyl triphosphate acetyl acetyl H nh ₂ OH triphosphate acetyl acetyl H nh ₂ F triphosphate acetyl acetyl H ' nh ₂ Cl

• · · · · ·

7G +

R ¹ R ² R ³ X ¹ X ² Y Η H H H Cl H Η H H H Cl H Η H H H Cl NH ₂ Η H H H Cl NH-cyclopropyl Η H H H Cl NH-methyl Η H H H Cl NH-ethyl Η H H H Cl NH-acetyl Η H H H Cl OH Η H H H Cl About me Η H H H Cl OEt Η H H H Cl O-Cyclopropyl Η H H H Cl O-acetyl Η H H H Cl SH Η H H H Cl SMe Η H H H Cl SEt Η H H H Cl S-cyclopropyl monophosphate H H H Cl nh ₂ monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H Cl NH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl O-acetyl monopho sphate H H H Cl About me monophosphate H H H Cl OEt monophosphate H H H Cl O-Cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl nh ₂

4 (t

R ¹ R ² R ^J X ¹ X * - Y diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H Cl OH diphosphate H H H Cl O-acetyl diphosphate H H H Cl About me diphosphate H H H Cl OEt diphosphate H H H Cl O-Cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphate H H H Cl nh ₂ triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl About me triphosphate H H H Cl OEt triphosphate H H H Cl O-Cyclopropyl triphosphate H H H Cl O-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphate H H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphate monophosphate monophosphate H Cl NH ₂ monophosphate monophosphate monophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H Cl OH diphosphate diphosphate diphosphate H * Cl nh ₂

• ·

Ml

R ¹ R ² R ^J X ¹ X ² Y diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate H Cl NH ₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH H H H F Cl NH ₂ H H H F Cl NH-cyclopropyl H H H F Cl OH H H H Cl Cl NH ₂ H H H Cl Cl NH-cyclopropyl H H H Cl Cl OH H H H Br Cl nh ₂ H H H Br Cl NH-cyclopropyl H H H Br Cl OH H H H nh ₂ Cl nh ₂ H H H nh ₂ Cl NH-cyclopropyl H H H nh ₂ Cl OH H H H SH Cl nh ₂ H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl nh ₂ acetyl H H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl nh ₂ acetyl H H F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl nh ₂ H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetyl acetyl H Cl NH ₂ acetyl acetyl acetyl H Cl NH-cyclopropyl

· · · · · · ·

ΊΙΟ

R ¹ R ² R ³ X ¹ X ¹ Y acetyl acetyl acetyl IH ! Cl OH monophosphate acetyl acetyl H Cl nh ₂ monophosphate acetyl acetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H Cl nh ₂ diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetyl acetyl H Cl nh ₂ triphosphate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H Cl OH ^H H H ^H Cl nh ₂ H H H H Cl NH-cyclopropyl H H H H Cl OH H H H H Br nh ₂ H H H H Br NH-cyclopropyl H H H H Br OH

Nucleosides of formula V can also be prepared using appropriate sugars and pyrimidine or purine bases.

R ¹ R ² R ³ X ¹ Y H H H H , H H H H H nh ₂

R ¹ R ² R ³ T— Y Η H H H NH-cyclopropyl Η H H H 1 NH-methyl Η H H H NH-ethyl Η H H H NH-acetyl Η H H H OH Η H H H About me Η H H H OEt Η H H H O-Cyclopropyl Η H H H O-acetyl Η H H H SH Η H H H SMe Η H H H SEt Η H H H S-cyclopropyl monophosphate H H H nh ₂ monophosphate H H H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H O-acetyl monophosphate H H H About me monophosphate H H H OEt monophosphate H H H O-Cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate H H H S-cyclopropyl diphosphate H H H NH ₂ diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl

zines

R ¹ R ² R ³ X ¹ Y diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H About me diphosphate H H H OEt diphosphate H H H O-Cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H H H SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH ₂ triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphate H H H About me triphosphate H H H OEt triphosphate H H H O-Cyclopropyl triphosphate H H H O-acetyl triphosphate H H H SH triphosphate H H H SMe triphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H nh ₂ diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OH triphosphate triphosphate triphosphate H nh ₂

···· · ·· ·· ·· · · · · · ·

R ¹ R ² R ³ X ¹ Y triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F nh ₂ H H H F NH-cyclopropyl H H H F OH H H H Cl nh ₂ H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH ₂ H H H Br NH-cyclopropyl H H H Br OH H H H nh ₂ nh ₂ H H H nh ₂ NH-cyclopropyl H H H nh ₂ OH H H H SH nh ₂ H H H SH NH-cyclopropyl H H H SH OH acetyl H H H nh ₂ acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F nh ₂ acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH ₂ H acetyl acetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH ₂ acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphate acetyl acetyl H NH ₂ monophosphate acetyl acetyl H NH-cyclopropyl

//? Ý

^R1 R ² R ² x ¹ - Y mónophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH ₂ diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH Triphosphate acetyl acetyl H NH ₂ triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH

Nucleosides of formula X can also be prepared using the appropriate sugars and pyrimidine or purine bases.

(X)

R ¹ R ² R ³ R ⁶ Base H H H ch ₃ 0 2,4-0- Diacetyluracil H H H ch ₃ 0 Hypoxanthine H H H ch ₃ 0 2,4-0- Diacetylthymine H H H ch ₃ 0 Thymine H H H ch ₃ 0 Cytosine H H H ch ₃ 0 4- (N-mono- acetyl) cytosine H H H ch ₃ 0 4- (N, N-) diacetyl) cytosine H H H ch ₃ 0 Uráčil

* I * · · · · • * * »* * * ·

R ¹ R ² R * R ^b X Base H H H ch ₃ 0 5-Fluorouracil H H H ch ₃ with 2,4-0- Diacetyluracil H H H ch ₃ with Hypoxanthine H H H ch ₃ with 2,4-0- Diacetylthymine H H H ch ₃ with Thymine H H H ch ₃ with Cytosine H H H ch ₃ with 4- (N-mono- acetyl) cytosine H H H ch ₃ with 4- (N, N-) diacetyl) cytosine H H H ch ₃ with Uráčil H H H ch ₃ with 5-Fluorouracil monophosphate H H ch ₃ 0 2,4-0- Diacetyluracil monophosphate H H ch ₃ 0 Hypoxanthine monophosphate H H ch ₃ 0 2,4-0- Diacetylthymine monophosphate H H ch ₃ 0 Thymine monophosphate H H ch ₃ 0 Cytosine monophosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ 0 Uráčil monophosphate H H ch ₃ 0 5-Fluorouracil monophosphate H H ch ₃ with 2,4-0- · Diacetyluracil monophosphate H H ch ₃ with Hypoxanthine monophosphate H H ch ₃ . with 2,4-0- Diacetylthymine

It * · * ♦

R ¹ R ² Ø ³ - R ⁶ X Base monophosphate H H ch ₃ with Thymine monophosphate H H ch ₃ with Cytosine monophosphate H H ch ₃ with 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ with 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ with Uráčil monophosphate H H ch ₃ with 5-Fluorouracil diphosphate H H ch ₃ 0 2,4-O- Diacetyluracil diphosphate H H ch ₃ 0 Hypoxanthine diphosphate H H ch ₃ 0 2,4-O- Diacetylthymine diphosphate H H ch ₃ 0 Thymine diphosphate H H ch ₃ 0 Cytosine diphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine diphosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine diphosphate H H ch ₃ 0 Uráčil diphosphate H H ch ₃ 0 5-Fluorouracil diphosphate H H ch ₃ with 2,4-O- Diacetyluracil diphosphate H H ch ₃ with Hypoxanthine diphosphate H H ch ₃ with 2,4-0- Diacetylthym / n diphosphate H H ch ₃ with Thymine diphosphate H H ch ₃ with Cytosine triphosphate H H ch ₃ 0 2,4-O- Diacetyluracil triphosphate H H ch ₃ 0 Hypoxanthine

· «1 1 1 1 1 1 1 1 * 1 1 9 * * 9

4 9 ta · 4 4 444449 4 4 »ί ·

4? Ř

R ³ R ² Ø ³ - R ⁶ '' X Base triphosphate H H ch ₃ 0 2,4-O- Diacetylthymine triphosphate H H ch ₃ 0 Thymine triphosphate H H ch ₃ 0 Cytosine triphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine triphosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine triphosphate H H ch ₃ 0 Uráčil triphosphate H H ch ₃ 0 5-Fluorouracil triphosphate H H ch ₃ with 2,4-O- Diacetyluracil triphosphate H H ch ₃ with Hypoxanthine triphosphate H H ch ₃ with 2,4-O- Diacetylthymine triphosphate H H ch ₃ with Thymine triphosphate H H ch ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ 0 2,4-O- Diacetyluracil monophosphate monophosphate monophosphate cf ₃ 0 Hypoxanthine monophosphate monophosphate monophosphate cf ₃ 0 2,4-O- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ 0 Thymine monophosphate monophosphate monophosphate cf ₃ O Cytosine monophosphate monophosphate monophosphate cf ₃ 0 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ 0 Uráčil monophosphate monophosphate monophosphate cf ₃ 0 5-Fluorouracil monophosphate monophosphate monophosphate cf ₃ « with 2,4-O- Diacetyluracil

F * * ♦ © © © © © ©;; «« © 9 9 9 9 9 9 9 9 9 9 9 9 f f f f f f f f f

R ¹ R ² R ³ R ⁶ X Base monophosphate monophosphate monophosphate cf ₃ 1 with Hypoxanthine monophosphate monophosphate monophosphate cf ₃ with 2,4-0- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ with Thymine monophosphate monophosphate monophosphate cf ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with Uráčil monophosphate monophosphate monophosphate cf ₃ with 5-Fluorouracil acetyl acetyl acetyl cf ₃ 0 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl cf ₃ with 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl 0 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl with 4- (N, N-) diacetyl) cytosine H H H ch ₃ 0 2- (N, N-diacetyl) - guanine H H H ch ₃ 0 6-O-acetyl guanine H H H ch ₃ 0 8-fluoroguanine H H H ch ₃ 0 guanine H H H ch ₃ 0 6- (N, N-diacetyl) adenine H H H ch ₃ 0 2-Fluoroadenine H H H ch ₃ 0 8-Fluoroadenine H H H ch ₃ 0 2,8-difluoro- adenine H H H ch ₃ 0 adenine

····· ············································

R ¹ R ² R ³ R ^b X Base Η H H ch ₃ with 2- (N, N-diacetyl) - guanine Η H H ch ₃ with 6-O-acetyl guanine Η H H ch ₃ with 8-fluoro-guanine Η H H ch ₃ with guanine Η H H ch ₃ with 6- (N, N-diacetyl) adenine Η H H ch ₃ with 2-Fluoroadenine Η H H ch ₃ with 8-Fluoroadenine Η ( H H ch ₃ with 2, S-difluoro- adenine Η H H ch ₃ with adenine monophosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine monophosphate H H ch ₃ 0 6-O-acetyl guanine monophosphate H H ch ₃ 0 8-fluoroguanine monophosphate H H ch ₃ 0 guanine monophosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine monophosphate H H ch ₃ 0 2-Fluoroadenine monophosphate H H ch ₃ 0 8-Fluoroadenine monophosphate H H ch ₃ 0 2,8-difluoro- adenine monophosphate H H ch ₃ 0 adenine monophosphate H H ch ₃ with 2- (N, N-diacetyl) - gnanine monophosphate H H ch ₃ with 6-O-acetyl guanine monophosphate H H ch ₃ ... with 8-fluoroguanine monophosphate H H ch ₃ with guanine

····· · ·· · ···························· ···

R ¹ R ² R ³ R ^b X Base monophosphate H H ch ₃ with 6- (N, N-diacetyl) adenine monophosphate H H ch ₃ with 2-Fluoroadenine monophosphate H H ch ₃ with 8-Fluoroadenine monophosphate H H ch ₃ with 2,8-difluoro- adenine monophosphate H H ch ₃ with adenine diphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine diphosphate H H ch ₃ O 6-O-acetyl guanine diphosphate H H ch ₃ O 8-fluoroguanine diphosphate H H ch ₃ 0 guanine diphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ 0 2-Fluoroadenine diphosphate H H ch ₃ 0 8-Fluoroadenine diphosphate H H ch ₃ 0 2,8-difluoro- adenine diphosphate H H ch ₃ 0 adenine diphosphate H H ch ₃ with 2- (N, N-diacetyl) - guanine diphosphate H H ch ₃ with 6-O-acetyl guanine diphosphate H H ch ₃ with 8-fluoroguanine diphosphate H H ch ₃ with guanine diphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ with 2-Fluoroadenine diphosphate H H ch ₃ with 8-Fluoroadenine diphosphate H H ch ₃ with 2,8-difluoro- adenine

····· · ·· · · · · · · · · · · * * * * · * * * * * * ··

R ¹ R ² R ³ R ⁶ X Base diphosphate H H ch ₃ with adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine triphosphate H H ch ₃ 0 6-O-acetyl guanine triphosphate H H ch ₃ 0 8-fluoroguanine triphosphate H H ch ₃ 0 guanine triphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ 0 2-Fluoroadenine triphosphate H H ch ₃ 0 8-Fluoroadenine triphosphate H H ch ₃ 0 2,8-difluoro- adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine triphosphate H H ch ₃ with 6-O-acetyl guanine triphosphate H H ch ₃ with 8-fluoroguanine triphosphate H H ch ₃ with guanine triphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ with 2-Fluoroadenine triphosphate H H ch ₃ with 8-Fluoroadenine triphosphate H H ch ₃ with 2,8-difluoro- adenine triphosphate H H ch ₃ with adenine monophosphate monophosphate monophosphate cf ₃ 0 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ 0 6-O-acetyl guanine monophosphate monophosphate monophosphate cf ₃ . 0 8-fluoroguanine monophosphate monophosphate monophosphate cf ₃ 0 guanine

κ) Μ-

R ¹ R ² R ³ R X Base monophosphate monophosphate monophosphate cf ₃ 0 6- (N, N-diacetyl) adenine monophosphate monophosphate monophosphate | CF ₃ 0 2-Fluoroadenine monophosphate monophosphate monophosphate CF ₃ 0 8-Fluoroadenine monophosphate monophosphate monophosphate CF ₃ 0 2,8-difluoro- adenine monophosphate monophosphate monophosphate cf ₃ 0 adenine monophosphate monophosphate monophosphate cf ₃ with 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ with 6-O-acetyl guanine monophosphate monophosphate monophosphate cf ₃ with 8-fluoroguanine monophosphate monophosphate monophosphate cf ₃ with guanine monophosphate monophosphate monophosphate cf ₃ with 6- (N, N-diacetyl) adenine monophosphate monophosphate monophosphate cf ₃ with 2-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 8-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 2,8-difiuoro- adenine monophosphate monophosphate monophosphate cf ₃ with adenine acetyl acetyl acetyl! cf ₃ 0 guanine acetyl acetyl acetyl j čf ₃ with guanine acetyl acetyl acetyl j and and 2-bromo- vinyl 0 ¹ guanine acetyl acetyl acetyl 2-bromo- vinyl with guanine

By using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula XI can also be prepared.

I * · · · ·

OR ² R ⁷ (XI)

R ¹ R ² R ⁷ R ^b X Base H H H ch ₃ 0 2,4-O-Diacetyluracil H H H ch ₃ 0 Hypoxanthine H H H ch ₃ 0 2,4-O-Diacetylthymine H H H ch ₃ 0 Thymine H H H ch ₃ 0 Cytosine H H H ch ₃ 0 4- (N-mono- acetyl) cytosine H H H ch ₃ 0 4- (N, N-diacetyl) cytosine H H H ch ₃ 0 Uráčil H H H ch ₃ 0 5-Fluorouracil H H H ch ₃ with 2,4-O-Diacetyluracil H H H ch ₃ with Hypoxanthine H H H ch ₃ with 2,4-O-Diacetylthymine H H H ch ₃ with Thymine H H H ch ₃ with Cytosine H H H ch ₃ with 4- (N-mono-acetyl) cytosine H H H ch ₃ with 4- (N, N-diacetyl) cytosine H H H ch ₃ with Uráčil H H H ch ₃ with 5-Fluorouracil ch ₃ monophosphate H H ch ₃ 0 2,4-O-Diacetyluracil monophosphate H H ch ₃ 0 Hypoxanthine monophosphate H H ch ₃ 0 2,4-O-Diacetylthymine

«·

R ¹ R ² R ⁷ R ⁶ X Base monophosphate H H ch ₃ 0 Thymine monophosphate H H ch ₃ 0 Cytosine monophosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ 0 4- (N, N-diacetyl) cytosine monophosphate H H ch ₃ 0 Uráčil monophosphate H H ch ₃ 0 5-Fluorouracil monophosphate H H ch ₃ with 2,4-O-Diacetyluracil monophosphate H H ch ₃ with Hypoxanthine monophosphate H H ch ₃ with 2,4-O-Diacetylthymine monophosphate H H ch ₃ with Thymine monophosphate H H ch ₃ with Cytosine monophosphate H H ch ₃ with 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ with 4- (N, N-diacetyl) cytosine monophosphate H H ch ₃ with Uráčil monophosphate H H ch ₃ with 5-Fluorouracil diphosphate H H ch ₃ 0 2,4-O-Diacetylurac diphosphate H H ch ₃ 0 Hypoxanthine diphosphate H H ch ₃ 0 2,4-O-Diacetylthymme diphosphate H H ch ₃ 0 Thymine diphosphate H H ch ₃ 0 Cytosine diphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine diphosphate H H ch ₃ 0 4- (N, N-diacetyl) cytosine diphosphate H H ch ₃ 0 Uráčil diphosphate H H ch ₃ 0 5-Fluorouracil diphosphate H H ch ₃ with 2,4-O-Diacetyluracil diphosphate H H ch ₃ with Hypoxanthine diphosphate H H ch ₃ with 2,4-O-Diacetylthym diphosphate H H ch ₃ with Thymine

Ί & 5 ~

R ¹ R ² R ⁷ R ⁴ X Base diphosphate H H ch ₃ with Cytosine triphosphate H H ch ₃ 0 2,4-O-Diacetyluracil triphosphate H H ch ₃ 0 Hypoxanthine triphosphate H H ch ₃ 0 2,4-O-Diacetylthymine triphosphate H H ch ₃ 0 Thymine triphosphate H H ch ₃ 0 Cytosine triphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine triphosphate H H ch ₃ 0 4- (N, N-diacetyl) cytos triphosphate H H ch ₃ 0 Uráčil triphosphate H H ch ₃ 0 5-Fluorouracil triphosphate H H ch ₃ with 2,4-O-Diacetyluracil triphosphate H H ch ₃ with Hypoxanthine triphosphate H H ch ₃ with 2,4-O-Diacetylthym triphosphate H H ch ₃ with Thymine triphosphate H H ch ₃ with Cytosine monophosphate monophosphate Br cf ₃ 0 2,4-O-Diacetyluracil monophosphate monophosphate Br cf ₃ 0 Hypoxanthine monophosphate monophosphate Br cf ₃ 0 2,4-O-Diacetylthymine monophosphate monophosphate Br cf ₃ 0 Thymine monophosphate monophosphate Br cf ₃ 0 Cytosine monophosphate monophosphate Br cf ₃ 0 4- (N-mono- acetyl) cytosine monophosphate monophosphate Br cf ₃ 0 4- (N, N-diacetyl) cytosine monophosphate monophosphate Br cf ₃ 0 Uráčil monophosphate monophosphate Br cf ₃ 0 5-Fluorouracil monophosphate monophosphate Br cf ₃ with 2,4-O-Diacetyluracil monophosphate monophosphate Br cf ₃ with Hypoxanthine monophosphate monophosphate Br cf ₃ with 2,4-O-Diacetylthymine monophosphate monophosphate Br cf ₃ with Thymine monophosphate monophosphate Br cf ₃ with Cytosine

· * »» »» »» »» »» »» »» »» »» »

R ¹ Ř ² R ⁷ R ⁴ X Base monophosphate monopho sphate Br cf ₃ with 4- (N-mono- acetyljcytosine monophosphate monophosphate Br cf ₃ with 4- (N, N-diacetyl) cytos monophosphate monophosphate Br cf ₃ with Uráčil monophosphate monophosphate Br cf ₃ with 5-Fluorouracil acetyl acetyl NO2 cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl acetyl NO2 cf ₃ with 4- (N2s-diacetyl) cytosine acetyl acetyl NO2 cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl acetyl NO2 2-bromo- vinyl with 4- (N, N-diacetyl) cytosine

Nucleosides of formula XII can also be prepared using the appropriate sugars and pyrimidine or purine bases.

(ΧΠ) where:

R ¹ R ⁴ X Base H ch ₃ 0 2,4-O-Diacetyluracil H ch ₃ 0 Hypoxanthine H ch ₃ 0 2,4-O-Diacetylthymine H ch ₃ 0 Thymine H ch ₃ 0 Cytosine H ch ₃ 0 4- (N-mono-acetyl) cytosine H ch ₃ 0 4- (N, N-diacetyl) cytosine H ch ₃ 0 Uráčil H ch ₃ 0 5-Fluorouracil

______MP

R ¹ R ⁶ X Base H ch ₃ with 2,4-O-Diacetyluracil H ch ₃ with Hypoxanthine H ch ₃ with 2,4-O-Diacetylthymine H ch ₃ with Thymine H ch ₃ with Cytosine H ch ₃ with 4- (N-mono-acetyl) cytosine H ch ₃ with 4- (N, N-diacetyl) cytosine H ch ₃ with Uráčil H ch ₃ with 5-Fluorouracil monophosphate ch ₃ 0 2,4-O-Diacetyluracil monophosphate ch ₃ 0 Hypoxanthine monophosphate ch ₃ 0 2,4-O-Diacetylthymine monophosphate ch ₃ 0 Thymine monophosphate ch ₃ 0 Cytosine monophosphate ch ₃ 0 4- (N-mono-acetyl) cytosine monophosphate ch ₃ 0 4- (N, N-diacetyl) cytosine monophosphate ch ₃ 0 Uráčil monophosphate ch ₃ 0 5-Fluorouracil monophosphate ch ₃ with 2,4-O-Diacetyluracil monophosphate ch ₃ with Hypoxanthine monophosphate ch ₃ with 2,4-O-Diacetylthymine monophosphate ch ₃ with Thymine monophosphate ch ₃ with Cytosine monophosphate ch ₃ with 4- (N-mono-acetyl) cytosine monophosphate ch ₃ with 4- (N, N-diacetyl) cytosine monophosphate ch ₃ with Uráčil monophosphate ch ₃ with 5-Fluorouracil diphosphate ch ₃ 0 2,4-O-Diacetyluracil diphosphate ch ₃ 0 Hypoxanthine diphosphate ch ₃ 0 2,4-O-Diacetylthymine diphosphate ch ₃ 0 Thymine

·· · »

R ¹ R ⁶ X Base diphosphate ch ₃ 0 Cytosine diphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine diphosphate ch ₃ 0 4- (NN-diacetyl) cytosine diphosphate ch ₃ 0 Uráčil diphosphate ch ₃ 0 5-Fluorouracil diphosphate ch ₃ with 2,4-O-Diacetyluracil diphosphate ch ₃ with Hypoxanthine diphosphate ch ₃ with 2,4-O-Diacetylthymine diphosphate ch ₃ with Thymine diphosphate ch ₃ with Cytosine triphosphate ch ₃ 0 2,4-O-Diacetyluracil triphosphate ch ₃ 0 Hypoxanthine triphosphate ch ₃ 0 2,4-O-Diacetylthymine triphosphate ch ₃ 0 Thymine triphosphate ch ₃ 0 Cytosine triphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine triphosphate ch ₃ 0 4- (N, N-diacetyl) cytosine triphosphate ch ₃ 0 Uráčil triphosphate ch ₃ 0 5-Fluorouracil triphosphate ch ₃ with 2,4-O-Diacetyluracil triphosphate ch ₃ with Hypoxanthine triphosphate ch ₃ with 2,4-O-Diacetylthymine triphosphate ch ₃ with Thymine triphosphate ch ₃ with Cytosine monophosphate cf ₃ 0 2,4-O-Diacetyluracil monophosphate cf ₃ 0 Hypoxanthine monophosphate cf ₃ 0 2,4-O-Diacetylthymine monophosphate cf ₃ 0 Thymine monophosphate cf ₃ 0 Cytosine monophosphate cf ₃ 0 4- (N-mono-acetyl) cytosine monophosphate cf ₃ 0 4- (N, N-diacetyl) cytosine

R ¹ R * X Base monophosphate cf ₃ 0 Uráčil monophosphate cf ₃ 0 5-Fluorouracil monophosphate cf ₃ S - 2,4-O-Diacetyluracil monophosphate cf ₃ with Hypoxanthine monophosphate cf ₃ with 2,4-O-Diacetylthymine monophosphate cf ₃ with Thymine monophosphate cf ₃ with Cytosine monophosphate cf ₃ with 4- (N-mono-acetyl) cytosine monophosphate cf ₃ with 4- (N, N-diacetyl) cytosine monophosphate cf ₃ with Uráčil monophosphate cf ₃ with 5-Fluorouracil acetyl cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl cf ₃ with 4- (N, N-diacetyl) cytosine acetyl 2-bromo-vinyl 0 4- (N, N-diacetyl) cytosine acetyl 2-bromo-vinyl with 4- (N, N-diacetyl) cytosine

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula XVII can also be prepared.

R ¹ R R ⁷ X Base R * r ¹⁵ H ch ₃ Η 0 2,4-O-Diacetyluracil NHAc Me H ch ₃ Η 0 Hypoxanthine NH2 Me H ch ₃ Η 0 2,4-O-Diacetylthymine NHAc Me H ch ₃ Η 0 Thymine NH2 Me

MO

R ¹ R ⁶ R ⁷ X Base R ^s H ch ₃ H 0 Cytosine NH2 Me H ch ₃ H 0 4- (N-mono-acetyl) cytosine NHAc Me H ch ₃ H 0 4- (N, N-diacetyl) cytosine NHAc Me H ch ₃ H 0 Uráčil NH2 Me H ch ₃ H 0 5-Fluorouracil NH2 Me H ch ₃ H with 2,4-O-Diacetyluracil NHAc Me H ch ₃ H with Hypoxanthine NH2 Me H ch ₃ H with 2,4-O-Diacetylthymine NHAc Me H ch ₃ H with Thymine NH2 Me H ch ₃ H with Cytosine NH2 Me H ch ₃ H with 4- (N-mono-acetyl) cytosine NHAc Me H ch ₃ H with 4- (N, N-diacetyl) cytosine NHAc Me H ch ₃ H with Uráčil ΝΉ2 Me H ch ₃ H with 5-Fluorouracil NH2 Me monophosphate ch ₃ H 0 2,4-O-Diacetyluracil NHAc Me monophosphate ch ₃ H 0 Hypoxanthine NH2 Me monophosphate ch ₃ H 0 2,4-0 -Diacetylthymine NHAc Me monophosphate ch ₃ H 0 Thymine NH2 Me monophosphate ch ₃ H 0 Cytosine NH2 Me monophosphate ch ₃ H O 4- (N-mono-acetyl) cytosine NHAC Me monophosphate ch ₃ H 0 4- (N, N-diacetyl) cytosine NHAc Me monophosphate ch ₃ H 0 Uráčil NH2 Me monophosphate ch ₃ H 0 5-Fluorouracil NH2 Me monophosphate ch ₃ H with 2,4-O-Diacetyluracil NHAc Me monophosphate ch ₃ H with Hypoxanthine ΝΉ2 Me monophosphate ch ₃ H with 2,4-O-Diacetylthymine NHAc Me monophosphate ch ₃ H with Thymine NH2 Me monophosphate ch ₃ H with Cytosine NH2 Me monophosphate CH ₃ H with 4- (N-mono-acetyl) cytosine NHAc Me monophosphate ch ₃ H with 4- (N 1 -diacetyl) cytosine NHAc Me monophosphate ch ₃ H with Uráčil NH2 Me

R ¹ R ⁶ R ⁷ X Base R ^s r ¹ ” monophosphate ch ₃ H with 5-Fluorouracil NH2 Me diphosphate ch ₃ H 0 2,4-O-Diacetyluracil NHAc Me diphosphate ch ₃ H 0 Hypoxanthine NH2 Me diphosphate ch ₃ H 0 2,4-O-Diacetylthymine NH2 Me diphosphate ch ₃ H 0 Thymine NH2 Me diphosphate ch ₃ H 0 Cytosine NH2 Me diphosphate ch ₃ H 0 4- (N-mono-acetyl) cytosine NHAc Me diphosphate ch ₃ H 0 4- (N, N-diacetyl) cytos NHAc Me diphosphate ch ₃ H 0 Uráčil NH2 Me diphosphate ch ₃ H 0 5-Fluorouracil NH2 Me diphosphate ch ₃ H with 2,4-O-Diacetyluracil NH2 Me diphosphate ch ₃ H with Hypoxanthine NH2 Me diphosphate ch ₃ H with 2,4-O-Diacetylthymine NHAc Me diphosphate ch ₃ H with Thymine NH2 Me diphosphate ch ₃ H with Cytosine NH2 Me triphosphate ch ₃ H 0 2,4-O-Diacetyluracil NHAc Me triphosphate ch ₃ H 0 Hypoxanthine NHAc Me triphosphate ch ₃ H 0 2,4-O-Diacetylthymine NHAc Me triphosphate ch ₃ H 0 Thymine NH2 Me triphosphate ch ₃ H 0 Cytosine NH2 Me triphosphate ch ₃ H 0 4- (N-mono-acetyl) cytosine NHAc Me triphosphate ch ₃ H 0 4- (N, N-diacetyl) cytosine NH2 Me triphosphate ch ₃ H 0 Uráčil NH2 Me triphosphate ch ₃ H 0 5-Fluorouiacil NH2 Me triphosphate ch ₃ H with 2,4-O-Diacetyluracil NH2 Me triphosphate ch ₃ H with Hypoxanthine NH2 Me triphosphate ch ₃ H with 2,4-O-Diacetylthymine NH2 Me triphosphate ch ₃ H with Thymine NH2 Me triphosphate ch ₃ H with Cytosine NH2 Me monophosphate cf ₃ H 0 2,4-O-Diacetyluracil NH2 Me monophosphate cf ₃ H 0 Hypoxanthine NH2 Me

• · · · ·

ML

R ¹ • R ^ů R ' X Base R ⁹ IF monophosphate cf ₃ H 0 2,4-O-Diacetylthymme NH2 Me monophosphate cf ₃ H 0 Thymine NH2 Me monophosphate cf ₃ H 0 Cytosine NH2 Me monophosphate cf ₃ H 0 4- (N-mono-acetyl) cytosine NH2 Me monophosphate cf ₃ H 0 4- (Nd7-acetyl) cytosme NH2 Me monophosphate cf ₃ H 0 Uráčil NH2 Me monophosphate cf ₃ H 0 5-Fluorouracil NH2 Me monophosphate cf ₃ H with 2,4-O-Diacetyluracil ΝΈ2 Me monophosphate cf ₃ H with Hypoxanthine NH2 Me monophosphate cf ₃ H with 2,4-O-Diaceiyithymine ΝΉ2 Me monophosphate cf ₃ H with Thymine NH2 Me monophosphate cf ₃ H with Cytosine NH2 Me monophosphate cf ₃ H with 4- (N-mono-acetyl) cytosine NH2 Me monophosphate cf ₃ - H with 4- (N, N-diacetyl) cytosine NH2 Me monophosphate cf ₃ H with Uráčil NH2 Me monophosphate cf ₃ H with 5-Fluorouracil NH2 Me acetyl ch ₃ H 0 4- (N, N-diacetyl) cytosine H Br acetyl ce ₃ H with 4- (N, N-acetyl) cytosine H Br acetyl ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Br acetyl ce ₃ OH with 4- (N, N-diacetyl) cytosine H Br

Example 3. Preparation of 3'-C-methylriboadenine

The compound is prepared according to R. F. Nutt,

M.J. Dickinson, F.W. Holly, and E. Walton, Branched-chain sugar nucleosides. III. 3'-C-methyiadenine, J. Org. Chem. 1968, 33, 1789-1795, Scheme 9.

·· * ·

Scheme 9

-0- ^ bc ^Sz0 ~ 1R-O6 O, ti

OH OH

-0CH,

R = CH ₃

NH,

NHBz

N.

N ^BzO ~ lKo <\\

NN.

^ N e, f ^Bz ° - [R ₀ .

OH OH and I

BzO BzO och ₃

OBz OBz (a) RuO ₂ / NaIO ₄ , (b) MeMgI / TiCl ₄ , (c) HCl / MeOH / H ₂ O, (d) BzCl / pyridine, (e) AcBr, HBr / AcOH, (f) chlorine β-benzamidopurine derivative, (g) NH ₃ / MeOK.

Nucleosides of formula III can also be prepared using the appropriate sugars and pyrimidine or purine bases.

R ¹ R ² Ř ³ X ¹ X ² Y H H H H H H H H H H H nh ₂ H H H H H NH-cyciopropyl H H H H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH

R ¹ Ř ² R ³ X ¹ X ² Y Η H H H H About me Η H H H H OEt Η H H H H O-Cyclopropyl Η H H H H O-acetyl Η H H H H SH Η H H H H SMe Η H H H H SEt Η H H H H S-cyclopropyl Η H H H H F Η H H H H Cl Η H H H H Br Η H H H H AND monophosphate H H H H nh ₂ monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropyl monophosphate H H H H NH-methyl monophosphate H H H H NH-ethyl monophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate H H H H About me monophosphate H H H H OEt monophosphate H H H H O-Cyclopropyl monophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H H SEt monophosphate H H H H S-cyclopropyl monophosphate H H H H F monophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H H AND diphosphate H H H H NH ₂

·· · · ««

R ¹ R ² R ³ and?- 'x ⁵ Y diphosphate H H H H NH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphate H H H H About me diphosphate H H H H OEt diphosphate H H H H O-Cyclopropyl diphosphate H H H H SH diphosphate H H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H H H H Cl diphosphate H H H H Br diphosphate H H H H AND triphosphate H H H H nh ₂ triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H H NH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OH triphosphate H H H H About me triphosphate H H H H OEt triphosphate H H H H O-Cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H H SEt triphosphate H H H H S-cyclopropyl

A. A. A. A

Ί96

R ¹ R ² R ³ 'x ¹ X ² Y triphosphate H H H H F triphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H AND monophosphate monophosphate monophosphate H H nh ₂ monophosphate monophosphate monophosphate H H NH-cyclopropyl monophosphate monophosphate monophosphate H H OH monophosphate monophosphate monophosphate H H F monophosphate monophosphate monophosphate H H Cl diphosphate diphosphate diphosphate H H nh ₂ diphosphate diphosphate diphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphate diphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cl triphosphate triphosphate triphosphate H H nh ₂ triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate H H OH triphosphate triphosphate triphosphate H H F triphosphate triphosphate triphosphate H H Cl H H H F H nh ₂ H H H F H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH ₂ H H H Cl H NH-cyclopropyl H H H Cl H OH H H H Cl H F H H H Cl H Cl H H H Br H nh ₂ H H H Br H NH-cyclopropyl

 • 5

R ¹ R ² R ³ x ¹ - X ¹ Y Η H H Br H OH Η H H Br H F Η H H Br H Cl Η H H nh ₂ H NH ₂ Η H H nh ₂ H NH-cyclopropyl Η H H nh ₂ H OH Η H H nh ₂ H F Η H H nh ₂ H Cl Η H H SH H nh ₂ Η H H SH H NH-cyclopropyl Η H H SH H OH Η H H SH H F Η H H SH H Cl acetyl H H H H NH ₂ acetyl H H H H NH-cyclopropyl acetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H NH ₂ acetyl H H F H NH-cyclopropyl acetyl H H F H OH acetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H nh ₂ H acetyl acetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetyl acetyl acetyl H H nh ₂ acetyl acetyl acetyl H H NH-cyclopropyl acetyl acetyl acetyl H H OH

· A a a a a a a>>>>>>>>>>>>>>>>>>> · T · «· t

R ¹ R ² R ³ 'X ¹ X ¹ Y acetyl acetyl acetyl H H F acetyl acetyl acetyl ! ^H H Cl monophosphate acetyl acetyl H H nh ₂ monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetyl acetyl IH 1 H OH monophosphate acetyl acetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetyl acetyl H H nh ₂ diphosphate acetvl acetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphate acetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetyl acetyl H H nh ₂ triphosphate acetyl acetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H nh ₂ H H H H H nh ₂ nh ₂ H H H H nh ₂ NH-cyclopropyl H H H H nh ₂ NH-methyl H H H H nh ₂ NH-ethyl H H H H NHz NH-acetyl H H H H nh ₂ OH H H H H nh ₂ About me H H H H nh ₂ OEt H H H H nh ₂ O-Cyclopropyl H H H H nh ₂ O-acetyl H H H H nh ₂ SH H H H H nh ₂ SMe H H H H nh ₂ SEt

• «« «

part

R ¹ R ² R ³ X ¹ X ² Y H H H H nh ₂ S-cyclopropyl H H H H nh ₂ F H H H H nh ₂ Cl H H H H nh ₂ Br H H H H nh ₂ AND monophosphate H H H nh ₂ nh ₂ monophosphate H H H nh ₂ NH-acetyl monophosphate H H H nh ₂ NH-cyclopropyl monophosphate H H H nh ₂ NH-methyl monophosphate H H H nh ₂ NH-ethyl monophosphate H H H nh ₂ OH monophosphate H H H nh ₂ O-acetyl monophosphate H H H nh ₂ About me monophosphate H H H nh ₂ OEt monophosphate H H H nh ₂ O-Cyclopropyl monophosphate H H H nh ₂ SH monophosphate H H H nh ₂ SMe monophosphate H H H nh ₂ SEt monophosphate H H H nh ₂ S-cyclopropyl monophosphate H H H nh ₂ F monophosphate H H H nh ₂ Cl monophosphate H H H nh ₂ . Br monophosphate H H H nh ₂ AND diphosphate H H H nh ₂ nh ₂ diphosphate H H H nh ₂ NH-acetyl diphosphate H H H nh ₂ NH-cyclopropyl diphosphate H H H nh ₂ NH-methyl diphosphate H H H nh ₂ NH-ethyl diphosphate H · H H nh ₂ OH diphosphate H H H nh ₂ O-acetyl diphosphate H H H nh ₂ About me

····· · Μ · * * «« «« fr 4 4 4 4 4 4 4 4 * fr fr fr fr * fr fr fr fr fr fr * ·

2oo

R ¹ R ² R ³ X ¹ x ² - Y diphosphate H H H nh ₂ OEt diphosphate H H H nh ₂ O-Cyclopropyl diphosphate H H H. nh ₂ SH diphosphate H H H nh ₂ SMe diphosphate H H H nh ₂ SEt diphosphate H H H nh ₂ S-cyclopropyl diphosphate H H H nh ₂ F diphosphate H H H nh ₂ Cl diphosphate H H H nh ₂ Br diphosphate H H H nh ₂ AND triphosphate H H H nh ₂ nh ₂ triphosphate H H H nh ₂ NH-acetyl triphosphate H H H nh ₂ NH-cyclopropyl triphosphate H H H nh ₂ NH-methyl triphosphate H H H nh ₂ NH-ethyl triphosphate H H H nh ₂ OH triphosphate H H H nh ₂ About me triphosphate H H H nh ₂ OEt triphosphate H H H nh ₂ O-Cyclopropyl triphosphate H H H nh ₂ O-acetyl triphosphate H H H nh ₂ SH triphosphate H H H nh ₂ SMe triphosphate H H H nh ₂ SEt triphosphate H H H nh ₂ S-cyclopropyl triphosphate H H H nh ₂ F triphosphate H H H nh ₂ Cl triphosphate H H H nh ₂ Br triphosphate H H H nh ₂ AND monophosphate monophosphate monophosphate H nh ₂ nh ₂ monophosphate monophosphate monophosphate H nh ₂ NH-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ OH

* 0000 * * ύ 00 0 0 • 0 9 9 9

0 · · 0 · · «0 0« 0 • 00 · 000 0000 ttt ·

204

R ¹ R ² R ³ 'X ¹ X ² Y monophosphate monopho sphate monophosphate H nh ₂ F monophosphate monophosphate monophosphate H nh ₂ Cl diphosphate diphosphate diphosphate H nh ₂ nh ₂ diphosphate diphosphate diphosphate H nh ₂ NH-cyclopropyl diphosphate diphosphate diphosphate H nh ₂ OH diphosphate diphosphate diphosphate H nh ₂ F diphosphate diphosphate diphosphate H nh ₂ Cl triphosphate triphosphate triphosphate H nh ₂ nh ₂ triphosphate triphosphate triphosphate H nh ₂ NH-cyclopropyl triphosphate triphosphate triphosphate H nh ₂ OH triphosphate triphosphate triphosphate H nh ₂ F triphosphate triphosphate triphosphate H nh ₂ Cl H H H F nh ₂ nh ₂ H H H F nh ₂ NH-cyclopropyl H H H F nh ₂ OH H H H F nh ₂ F H H H F nh ₂ Cl H H H Cl nh ₂ nh ₂ H H H Cl nh ₂ NH-cyclopropyl H H H Cl nh ₂ OH H H H Cl nh ₂ F H H H Cl nh ₂ Cl H H H Br nh ₂ nh ₂ H H H Br nh ₂ NH-cyclopropyl H H H Br nh ₂ OH H H H Br nh ₂ F H H H Br nh ₂ Cl H H H nh ₂ nh ₂ nh ₂ H H H nh ₂ nh ₂ NH-cyclopropyl H H H nh ₂ nh ₂ OH H H H nh ₂ nh ₂ F

• ·

R ¹ R ² R ³ X ¹ X ² Y H H H nh ₂ nh ₂ Cl H H H SH nh ₂ nh ₂ H H H SH nh ₂ NH-cyclopropyl H H H SH nh ₂ OH H H H SH nh ₂ F H H H SH nh ₂ Cl acetyl H H H nh ₂ nh ₂ acetyl H H H nh ₂ NH-cyclopropyl acetyl H H H nh ₂ OH acetyl H H H nh ₂ F acetyl H H H nh ₂ Cl acetyl H H F nh ₂ nh ₂ acetyl H H F nh ₂ NH-cyclopropyl acetyl H H F nh ₂ OH acetyl H H F nh ₂ F acetyl H H F nh ₂ Cl H acetyl acetyl H nh ₂ nh ₂ H acetyl acetyl H nh ₂ NH-cyclopropyl H acetyl acetyl H nh ₂ OH H acetyl acetyl H nh ₂ F H acetyl acetyl H nh ₂ Cl acetyl acetyl acetyl H nh ₂ nh ₂ acetyl acetyl acetyl H nh ₂ NH-cyclopropyl acetyl acetyl acetyl H nh ₂ OH acetyl acetyl acetyl H nh ₂ F acetyl acetyl acetyl H nh ₂ Cl monophosphate acetyl acetyl H nh ₂ nh ₂ monophosphate acetyl acetyl H nh ₂ NH-cyclopropyl monophosphate acetyl acetyl H nh ₂ OH monophosphate acetyl acetyl H nh ₂ F monophosphate acetyl acetyl H nh ₂ Cl

2.D3

R ¹ R ² R ³ x ¹ 'x ³ - Y diphosphate acetyl acetyl H nh ₂ nh ₂ diphosphate acetyl acetyl H nh ₂ NH-cyclopropyl diphosphate acetyl acetyl H nh ₂ OH diphosphate acetyl acetyl H nh ₂ F diphosphate acetyl acetyl H nh ₂ Cl triphosphate acetyl acetyl H nh ₂ nh ₂ triphosphate acetyl acetyl H nh ₂ NH-cyclopropyl triphosphate acetyl acetyl H nh ₂ OH triphosphate acetyl acetyl H nh ₂ F triphosphate acetyl acetyl H nh ₂ Cl H H H H Cl H H H H H Cl H H H H H Cl nh ₂ H H H H Cl NH-cyclopropyl H H H H Cl NH-methyl H H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl About me H H H H Cl OEt H H H H Cl O-Cyclopropyl H H H H Cl O-acetyl H H 1 H H Cl SH H H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H H H Cl nh ₂ monophosphate H H H Cl NH-acetyl monophosphate H H H Cl NH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H Cl NH-ethyl

2.0H

R ¹ R ² R ³ X ¹ X ² Y monophosphate H H H Cl OH monophosphate H H H Cl O-acetyl monophosphate H H H Cl About me monophosphate H H H Cl OEt monophosphate H H H Cl O-Cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMe monophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyl diphosphate H H H Cl nh ₂ diphosphate H H H Cl NH-acetyl diphosphate H H H Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H Cl NH-ethyl diphosphate H H H Cl OH diphosphate H H H Cl O-acetyl diphosphate H H H Cl About me diphosphate H H H Cl OEt diphosphate H H H Cl O-Cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMe diphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphate H H H Cl NH ₂ triphosphate H H H Cl NH-acetyl triphosphate H H H Cl NH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H Cl NH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl About me triphosphate H H H Cl OEt

• · · · · · · · · · · ·

R ¹ R ² R ³ X ¹ X ² Y triphosphate H H H Cl O-Cyclopropyl triphosphate H H H Cl O-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphate H H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphate monophosphate monophosphate H Cl NH ₂ monophosphate monophosphate monophosphate H Cl NH-cyclopropyl monophosphate monophosphate monophosphate H Cl OH diphosphate diphosphate diphosphate H Cl nh ₂ diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphate diphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate H Cl NH ₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyl triphosphate triphosphate triphosphate H Cl OH H H H F Cl nh ₂ H H H F Cl NH-cyclopropyl H H H F Cl OH H H H Cl Cl NH ₂ H H H Cl Cl NH-cyclopropyl H H H Cl Cl OH H H H Br Cl nh ₂ H H H Br Cl NH-cyclopropyl H H H Br Cl OH H H H nh ₂ Cl nh ₂ H H H nh ₂ Cl NH-cyclopropyl H H H nh ₂ Cl OH H H H SH Cl nh ₂ H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl nh ₂

ZOG>

R ¹ R ² R ³ X ¹ x ² - Y acetyl H H l ^H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl nh ₂ acetyl H H ^F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl nh ₂ H acetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetyl acetyl H Cl NH ₂ acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetyl acetyl H Cl OH monophosphate acetyl acetyl H Cl NH ₂ 1 monophosphate 1 acetyl acetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OH diphosphate acetyl acetyl H Cl nh ₂ diphosphate acetyl acetyl H Cl NH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetyl acetyl H Cl nh ₂ triphosphate acetyl acetyl H Cl NH-cyclopropyl triphosphate acetyl acetyl H Cl OH H H H! H Cl nh ₂ H H ^H 1 H Cl NH-cyclopropyl H H h 1 H Cl OH H H ^H i H Br nh ₂ H H H | H Br NH-cyclopropyl H H H H Br OH

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula VI can also be prepared.

• ·

(VI)

R ¹ R ² R ³ Έ Y Η H H H H Η H H H nh ₂ Η H H H NH-cyclopropyl Η H H H NH-methyl Η H H H NH-ethyl Η H H H NH-acetyl Η H H H OH Η H H H About me Η H H H OEt Η H H H O-Cyclopropyl Η H H H O-acetyl Η H H H SH Η H H H SMe Η H H H SEt Η H H H S-cyclopropyl monophosphate H H H nh ₂ monophosphate H H H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphate H H H OH monophosphate H H H O-acetyl

2D #

R ¹ R ² R ³ X ¹ Y monophosphate H H H About me monophosphate H H H OEt monophosphate H H H O-Cyclopropyl monophosphate H H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate H H H S-cyclopropyl diphosphate H H H NH ₂ diphosphate H H H NH-acetyl diphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphate H H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyl diphosphate H H H About me diphosphate H H H OEt diphosphate H H H O-Cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H H H SEt diphosphate H H S-cyclopropyl triphosphate H H H nh ₂ triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphate H H H About me triphosphate H H H OEt triphosphate H H H O-Cyclopropyl triphosphate H H H O-acetyl

• ·

2W

R ¹ R ² Ř ³ X ¹ Y triphosphate H H H SH triphosphate H H H SMe triphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphate monophosphate monophosphate H nh ₂ monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphate monophosphate monophosphate H OH diphosphate diphosphate diphosphate H nh ₂ diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate ^H OH triphosphate triphosphate triphosphate H nh ₂ triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate H OH H H H F nh ₂ H H H F NH-cyclopropyl H H H F OH H H H Cl NH ₂ H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH ₂ H H H Br NH-cyclopropyl H H H Br OH H H H nh ₂ nh ₂ H H H nh ₂ NH-cyclopropyl H H H nh ₂ OH H H H SH nh ₂ H H H SH NH-cyclopropyl H H H SH OH acetyl H H H NH ₂ acetyl H H H NH-cyclopropyl acetyl H H H OH

Zfo

R ¹ R ² R ³ X ¹ Y acetyl H H F nh ₂ acetyl H H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H nh ₂ H acetyl acetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H nh ₂ acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphate acetyl acetyl H nh ₂ monophosphate acetyl acetyl H NH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetyl acetyl H nh ₂ diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl H OH triphosphate acetyl acetyl H nh ₂ triphosphate acetyl acetyl H NH-cyclopropyl triphosphate acetyl acetyl ^H OH

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula XIII can also be prepared.

kd &:

R ¹ R ² R ³ R " X Base H H H CH ₃ δη 2,4-O- Diacetyluracil H H H ch ₃ 0 Hypoxanthine

I

2M

R ¹ R ² R ³ R ⁶ X Base Η H H CH ₃ 0 2,4-O- Diacetylthymine Η H H ch ₃ 0 Thymine Η H H ch ₃ 0 Cytosine Η H H ch ₃ 0 4- (N-mono- acetyl) cytosine Η H H ch ₃ 0 4- (N, N-) diacetyl) cytosine Η H H ch ₃ 0 Uráčil Η H H ch ₃ 0 5-Fluorouracil Η H H ch ₃ with 2,4-0- Diacetyluraci Η H H ch ₃ with Hypoxanthine Η H H ch ₃ with 2,4-O- Diacetylthymine Η H H ch ₃ with Thymine Η H H ch ₃ with Cytosine Η H H ch ₃ with 4- (N-mono- acetyl) cytosine Η H H ch ₃ with 4- (N, N-) diacetyl) cytosine Η H H ch ₃ with Uráčil Η H H ch ₃ with 5-Fluorouracil monophosphate H H ch ₃ 0 2,4-O- Diacetyluracil monophosphate H H ch ₃ 0 Hypoxanthine monophosphate H H ch ₃ 0 2,4-0- Diacetylthym monophosphate H H ch ₃ 0 Thymine monophosphate H H ch ₃ 0 Cytosine monophosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine

• 4 · «• •« «« «« ««

R ¹ R ² R ³ R ⁶ X Base monophosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ 0 Uráčil monophosphate H H ch ₃ 0 5-Fluorouracil monophosphate H H ch ₃ with 2,4-O- Diacetyluracil monophosphate H H ch ₃ with Hypoxanthine monophosphate H H ch ₃ with 2,4-0- Diacetylthymizj monophosphate H H ch ₃ with Thymine monophosphate H H ch ₃ with Cytosine monophosphate H H ch ₃ with 4- (N-mono- acetyl) cytosine monophosphate H H ch ₃ with 4- (N, N-) diacetyl) cytosine monophosphate H H ch ₃ with Uráčil monophosphate H H ch ₃ with 5-Fluorouracil diphosphate H H ch ₃ 0 2,4-O- Diacetyluracil diphosphate H H ch ₃ 0 Hypoxanthine diphosphate H H ch ₃ 0 2,4-O- Diacetylthymine diphosphate H H ch ₃ 0 Thymine diphosphate H H ch ₃ 0 Cytosine diphosphate H H čh ₃ 0 4- (N-mono- acetyl) cytosine diphosphate H H ch ₃ 0 4- (N, N-) diacetyl) cytosine diphosphate H H ch ₃ 0 Uráčil diphosphate H H ch ₃ 0 5-Fluorouracil diphosphate H H ch ₃ with 2,4-O- Diacetyluracil

· »1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 η 1

R ¹ Ř ² R ³ R ⁶ X Base diphosphate H H ch ₃ with Hypoxanthine diphosphate H H ch ₃ with 2,4-0- Diacetylthym diphosphate H H ch ₃ with Thymine diphosphate H H ch ₃ with Cytosine triphosphate H H ch ₃ 0 2,4-O- Diacetyluracil triphosphate H H ch ₃ 0 Hypoxanthine triphosphate H H ch ₃ 0 2,4-O- Diacetylthymine triphosphate H H ch ₃ 0 Thymine triphosphate H H ch ₃ 0 Cytosine triphosphate H H ch ₃ 0 4- (N-mono- acetyl) cytosine triphosphate H H ch ₃ 0 4- (NJSÍ- diacetyl) cytosine triphosphate H H ch ₃ 0 Uráčil triphosphate H H ch ₃ 0 5-Fluorouracil triphosphate H H ch ₃ with 2,4-O- Diacetyluracil triphosphate H H ch ₃ with Hypoxanthine triphosphate H H ch ₃ with 2,4-O- Diacetylthymine triphosphate H H ch ₃ with Thymine triphosphate H H ch ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ 0 2,4-O- Diacetyluracil monophosphate monophosphate monophosphate cf ₃ 0 Hypoxanthine monophosphate monophosphate monophosphate cf ₃ 0 2,4-O- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ 0 Thymine monophosphate monophosphate monophosphate cf ₃ 0 Cytosine

F * ·· * ·

R ¹ R ² R ³ R ⁶ X Base monophosphate monophosphate monophosphate cf ₃ 0 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ 0 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ 0 Uráčil monophosphate monophosphate monophosphate cf ₃ 0 5-Fluorouracil monophosphate monophosphate monophosphate cf ₃ with 2,4-0- Diacetyluracil monophosphate monophosphate monophosphate cf ₃ with Hypoxanthine monophosphate monophosphate monophosphate cf ₃ with 2,4-0- Diacetylthymine monophosphate monophosphate monophosphate cf ₃ with Thymine monophosphate monophosphate monophosphate cf ₃ with Cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N-mono- acetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with 4- (N, N-) diacetyl) cytosine monophosphate monophosphate monophosphate cf ₃ with Uráčil monophosphate monophosphate monophosphate cf ₃ with 5-Fluorouracil acetyl acetyl acetyl cf ₃ 0 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl cf ₃ with 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl O 4- (N, N-) diacetyl) cytosine acetyl acetyl acetyl 2-bromo- vinyl with 4- (N, N-) diacetyl) cytosine H H H ch ₃ 0 2- (N, N-diacetyl) - guanine H H H ch ₃ 0 6-O-acetyl guanine H H H ch ₃ 0 8-fluoroguanine

• · · · · · · · · · · · · · · · ·

R ¹ R ² R ³ R i ^x Base H H H ch ₃ ⁰ guanine H H H ch ₃ ⁰ 6- (N, N-diacetyl) adenine H H H ch ₃ 0 2-Fluoroadenine H H H ch ₃ 0 8-Fluoroadenine H H H ch ₃ 0 2,8-difluoro- adenine H H H ch ₃ 0 adenine H H H ch ₃ with 2- (N, N-diacetyl) - guanine H H H ch ₃ with 6-O-acetyl guanine Í ^H H H ch ₃ with 8-fluoroguanine Í ^H H H ch ₃ with guanine i ^H H H ch ₃ with 6- (N, N-diacetyl) adenine H H H ch ₃ with 2-Fluoroadenine H H H ch ₃ with 8-Fluoroadenine H H H ch ₃ with 2,8-difluoro- adenine H H H ch ₃ with adenine monophosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine monophosphate H H ch ₃ 0 6-O-acetyl guanine monophosphate H H ch ₃ 0 8-fluoroguanine monophosphate H H ch ₃ 0 guanine monophosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine monophosphate H H ch ₃ O 2-Fluoroadenine monophosphate H H ch ₃ 0 8-Fluoroadenine

• · · · · ·

2½

R ¹ R ² R ³ R ^ó X Base monophosphate H H ch ₃ 0 2,8-difluoro- adenine monophosphate H H ch ₃ O adenine monophosphate H H ch ₃ with 2- (N, N-diacetyl) - guanine monophosphate H H ch ₃ with 6-O-acetyl guanine monophosphate H H ch ₃ with 8-Fluoro guanine monophosphate H H ch ₃ with guanine monophosphate H H ch ₃ with 6- (N, N-diacetyl) adenine monophosphate H H ch ₃ with 2-Fluoroadenine monophosphate H H ch ₃ with 8-Fiuoro adenine monophosphate H H ch ₃ with 2,8-difluoro- adenine monophosphate H H ch ₃ with adenine diphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine diphosphate H H ch ₃ 0 6-O-acetyl guanine diphosphate H H ch ₃ 0 8-Fluoro guanine diphosphate H H ch ₃ 0 guanine diphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ O 2-Fluoroadenine diphosphate H H ch ₃ 0 8-Fluoroadenine diphosphate H H ch ₃ 0 2,8-difluoro- adenine diphosphate H H ch ₃ 0 adenine diphosphate H H ch ₃ with 2- (N, N-diacetyl) - guanine

• · · ·

R ¹ R ² R ³ R ^é X Base diphosphate H H ch ₃ with 6-O-acetyl guanine diphosphate H H CHj with 8-fluoroguanine diphosphate H H ch ₃ with guanine diphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine diphosphate H H ch ₃ with 2-Fluoroadenine diphosphate H H ch ₃ with 8-Fluoroadenine diphosphate H H ch ₃ with 2,8-difluoro- adenine diphosphate H H ch ₃ with adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine triphosphate H H ch ₃ 0 6-O-acetyl guanine triphosphate H H ch ₃ 0 8-fluoroguanine triphosphate H H ch ₃ 0 guanine triphosphate H H ch ₃ 0 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ 0 2-Fluoroadenine triphosphate H H ch ₃ 0 8-Fluoroadenine triphosphate H H ch ₃ 0 2,8-difluoro- adenine triphosphate H H ch ₃ 0 2- (N, N-diacetyl) - guanine triphosphate H H ch ₃ with 6-O-acetyl guanine triphosphate H H ch ₃ with 8-fluoroguanine triphosphate H H ch ₃ with guanine triphosphate H H ch ₃ with 6- (N, N-diacetyl) adenine triphosphate H H ch ₃ with 2-Fluoroadenine ·

ML

R ¹ R ² R ³ R ^b X Base triphosphate H H ch ₃ with 8-Fluoroadenine triphosphate H H ch ₃ with 2,8-difluoro- adenine triphosphate H H ch ₃ with adenine monophosphate monophosphate monophosphate cf ₃ 0 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ 0 6-O-acetyl guanine monophosphate monophosphate monophosphate cf ₃ 0 8-fluoroguanine monophosphate monophosphate monophosphate cf ₃ 0 guanine monophosphate monophosphate monophosphate cf ₃ 0 6- (N, N-diacetyl) - adenine monophosphate monophosphate monophosphate cf ₃ 0 2-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ 0 8-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ 0 2,8-difluoro- adenine monophosphate monophosphate monophosphate cf ₃ 0 adenine monophosphate monophosphate monophosphate cf ₃ with 2- (N, N-diacetyl) - guanine monophosphate monophosphate monophosphate cf ₃ with 6-O-acetyl guanine monophosphate monophosphate monophosphate cf ₃ with 8-fluoroguanine monophosphate monophosphate monophosphate cf ₃ with guanine monophosphate monophosphate monophosphate cf ₃ with 6- (N, N-diacetyl) adenine monophosphate monophosphate monophosphate cf ₃ with 2-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 8-Fluoroadenine monophosphate monophosphate monophosphate cf ₃ with 2,8-difluoro- adenine monophosphate monophosphate monophosphate cf ₃ with adenine acetyl acetyl acetyl cf ₃ O guanine acetyl acetyl acetyl cf ₃ with guanine

R ¹ R ² R ^J R ^b X Base acetyl acetyl acetyl 2-bromo- vinyl 0 guanine acetyl acetyl acetyl 2-bromo- vinyl with guanine

Nucleosides of formula XIV can also be prepared using the appropriate sugars and pyrimidine or purine bases.

OR ² (XIV) where ·.

R ¹ R ² R ^b X Base 1 H H CH ₃ 0 2,4-O-Diacetyluracil ! H H CHj 0 Hypoxanthine ί H ^H ch ₃ 0 2,4-O-Diacetylthymine H H ch ₃ 0 Thymine H H ch ₃ 0 Cytosine H H ch ₃ 0 4- (N-mono-acetyl) cytosine H H ch ₃ 0 4- (N, N-diacetyl) cytosine H H ch ₃ 0 Uráčil H H čh ₃ 0 5-Fluorouracil H H ch ₃ with 2,4-O-Diacetyluracil H H ch ₃ with Hypoxanthine H H ch ₃ with 2,4-O-Diacetylthymine H H ch ₃ with Thymine H H ch ₃ with Cytosine H H ch ₃ with 4- (N-mono-acetyl) cytcsin

£ 20

R ¹ R ² R ‘ X Base H H ch ₃ with 4- (N, N-diacetyl) cytosine H H ch ₃ with Uráčil H H ch ₃ with 5-Fluorouracil monophosphate H ch ₃ 0 2,4-O-Diacetyluracil monophosphate H ch ₃ 0 Hypoxanthine monophosphate H ch ₃ 0 2,4-O-Diacetylthym monophosphate H ch ₃ 0 Thymine monophosphate H ch ₃ 0 Cytosine monophosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine monophosphate H ch ₃ 0 4- (N, N-diacetyl) cytos monophosphate H ch ₃ 0 Uráčil monophosphate H ch ₃ 0 5-Fluorouracil monophosphate H ch ₃ with 2,4-O-Diacetyluracil monophosphate H CH ₃ with Hypoxanthine monophosphate H ch ₃ with 2,4-O-Diacetylthym monophosphate H ch ₃ with Thymine monophosphate H ch ₃ with Cytosine monophosphate H ch ₃ with 4- (N-mono-acetyl) cytosine monophosphate H ch ₃ S ' 4- (N, N-diacetyl) cytosine monophosphate H ch ₃ with Uráčil monophosphate H ch ₃ with 5-Fluorouracil diphosphate H ch ₃ 0 2,4-O-Diacetyluracil diphosphate H ch ₃ 0 Hypoxanthine diphosphate H ch ₃ 0 2,4-O-Diacetylthymine diphosphate H ch ₃ 0 Thymine diphosphate H ch ₃ 0 Cytosine diphosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine diphosphate H ch ₃ 0 4- (N, N-diacetyl) cytosine diphosphate H ch ₃ 0 Uráčil diphosphate H ch ₃ 0 5-Fluorouracil diphosphate H ch ₃ with 2,4-O-Diacetyluracil

· 1 · · 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

R ¹ R ² R ^é X Base diphosphate H ch ₃ with Hypoxanthine diphosphate H ch ₃ with 2,4-O-Diacetylthymine diphosphate H ch ₃ with Thymine diphosphate H ch ₃ with Cytosine triphosphate H ch ₃ 0 2,4-O-Diacetyluracil triphosphate H ch ₃ 0 Hypoxanthine triphosphate H ch ₃ 0 2,4-O-Diacetylthymine triphosphate H ch ₃ 0 Thymine triphosphate H ch ₃ 0 Cytosine triphosphate H ch ₃ 0 4- (N-mono-acetyl) cytosine triphosphate H ch ₃ 0 4- (N, N-diacetyl) cytosine triphosphate H ch ₃ 0 Uráčil triphosphate H ch ₃ 0 5-Fluorouracil triphosphate H ch ₃ with 2,4-O-Diacetyluracil triphosphate H ch ₃ with Hypoxanthine triphosphate H ch ₃ with 2,4-O-Diacetylthymine triphosphate H ch ₃ with Thymine triphosphate H ch ₃ with Cytosine monophosphate monophosphate cf ₃ 0 2,4-O-Diacetyluracil monophosphate monophosphate cf ₃ 0 Hypoxanthine monophosphate monophosphate cf ₃ 0 2,4-O-Diacetylthymine monophosphate monophosphate cf ₃ 0 Thymine monophosphate monophosphate cf ₃ 0 Cytosine monophosphate monophosphate cf ₃ 0 4- (N-mono-acetyl) cytosine monophosphate monophosphate cf ₃ 0 4- (N, N-diacetyl) cytosine monophosphate monophosphate cf ₃ i 0 Uráčil monophosphate monophosphate cf ₃ 0 5-Fluorouracil monophosphate monophosphate cf ₃ with 2,4-O-Diacetyluracil monophosphate monophosphate cf ₃ with Hypoxanthine monophosphate monophosphate cf ₃ with 2,4-O-Diacetylthymine monophosphate monophosphate cf ₃ with Thymine

· · 9 9 * * * * * * * * «9 9 9 9 9 9 9 ···

22L

R ¹ R ² R ⁶ X Base monophosphate monophosphate cf ₃ WITH Cytosine monophosphate monophosphate cf ₃ with 4- (N-mono-acetyl) cytosine monophosphate monophosphate cf ₃ with 4- (N, N-diacetyl) cytosine monophosphate monophosphate cf ₃ with Uráčil monophosphate monophosphate cf ₃ with 5-Fluorouiacil acetyl acetyl cf ₃ 0 4- (N, N-diacetyl) cytosine acetyl acetyl cf ₃ with 4- (N, N-diacetyl) cytosine acetyl acetyl 2-bromo- vinyl 0 4- (N, N-diacetyl) cytosine acetyl acetyl 2-bromo- vinyí with 4- (N, N-diacetyl) cytosine

Using the appropriate sugars and pyrimidine or purine bases, nucleosides of formula XV can also be prepared.

R ⁴ (XV) where:

R ¹ R ⁴ X Base H ch ₃ 0 2,4-O-Diacetyluracil H ch ₃ 0 Hypoxanthine H ch ₃ 0 2. —O-Diacetylthymine H ch ₃ 0 Thymine H ch ₃ 0 Cytosine H ch ₃ 0 4- (N-ru _IO-OI acetyl) cytosine H ch ₃ 0 4- (N, N-diacetyl) cytosine H ch ₃ 0 Uráčil

I · * * »» ««

R ¹ R ⁶ X Base H ch ₃ 0 5-Fluorouracil H ch ₃ with 2,4-O-Diacetyluracil H ch ₃ with Hypoxanthine H ch ₃ with 2,4-O-Diacetylthymine H ch ₃ with Thymine H ch ₃ with Cytosine H ch ₃ with 4- (N-mono-acetyl) cytosine H ch ₃ with 4- (N, N-diacetyl) cytosine H ch ₃ with Uráčil H ch ₃ with 5-Fluorouracil monophosphate ch ₃ 0 2,4-O-Diacetyluracil monophosphate ch ₃ 0 Hypoxanthine monophosphate ch ₃ 0 2,4-O-Diacetylthymine monophosphate ch ₃ 0 Thymine monophosphate ch ₃ 0 Cytosine monophosphate ch ₃ 0 4- (N-mono-acetyl) cytosine monophosphate ch ₃ 0 4- (N, N-diacetyl) cytosine monophosphate ch ₃ 0 Uráčil monophosphate ch ₃ 0 5-Fluorouracil monophosphate ch ₃ with 2,4-O-Diacetyluracil monophosphate ch ₃ with Hypoxanthine monophosphate ch ₃ with 2,4-O-Diacetylthymine monophosphate ch ₃ with Thymine monophosphate ch ₃ with Cytosine monophosphate ch ₃ with 4- (N-mono-acetyl) cytosine monophosphate ch ₃ with 4- (N, N-diacetyl) cytosine monophosphate ch ₃ with Uráčil monophosphate ch ₃ with 5-Fluorouracil diphosphate ch ₃ 0 2,4-O-Diacetyluracil diphosphate ch ₃ 0 Hypoxanthine diphosphate ch ₃ 0 2,4-O-Diacetylthymine

tf · · »·

R ¹ R ⁶ X Base diphosphate ch ₃ 0 Thymine diphosphate ch ₃ 0 Cytosine diphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine diphosphate ch ₃ 0 4- (N, N-diacetyl) cytosine diphosphate ch ₃ 0 Uráčil diphosphate ch ₃ 0 5-Fluorouracil diphosphate ch ₃ with 2,4-O-Diacetyluracil diphosphate ch ₃ with Hypoxanthine diphosphate ch ₃ with 2,4-O-Diacetylthymine diphosphate ch ₃ with Thymine diphosphate ch ₃ with Cytosine triphosphate ch ₃ 0 2,4-O-Diacetyluracil triphosphate ch ₃ 0 Hypoxanthine triphosphate ch ₃ 0 2,4-O-Diacetylthymine triphosphate ch ₃ 0 Thymine triphosphate ch ₃ 0 Cytosine triphosphate ch ₃ 0 4- (N-mono-acetyl) cytosine triphosphate ch ₃ 0 4- (N, N-diacetyl) cytosine triphosphate ch ₃ 0 Uráčil triphosphate ch ₃ 0 5-Fluorouracil triphosphate ch ₃ with 2,4-O-Diacetyluracil triphosphate ch ₃ with Hypoxanthine triphosphate ch ₃ with 2,4-O-Diacetylthymine triphosphate ch ₃ with Thymine triphosphate ch ₃ with Cytosine monophosphate cf ₃ 0 2,4-O-Diacetyluracil monophosphate cf ₃ 0 Hypoxanthine monophosphate cf ₃ 0 2,4-O-Diacetylthymine monophosphate cf ₃ 0 Thymine monophosphate cf ₃ 0 Cytosine monophosphate cf ₃ 0 4- (N-mono-acetyl) cytosine

····

99 »9» »* 9 9

9 «4 4 - t t t t t 9 9 - - - - - - - - - - -

R ¹ R ⁶ X Base monophosphate cf ₃ 0 4- (NN'-hiacetyl) cytosme monophosphate cf ₃ 0 Uráčil monophosphate cf ₃ 0 5-Fiuorouracil monophosphate cf ₃ with 2,4-O-Diacetyluracil monophosphate cf ₃ with Hypoxanthine monophosphate cf ₃ with 2,4-O-Diacetylthymine monophosphate cf ₃ with Thymine monophosphate cf ₃ with Cytosine monophosphate cf ₃ with 4- (N-mono-acetyl) cytosine monophosphate cf ₃ WITH 4- (N-Hiacetyl) cytosine monophosphate cf ₃ with Uráčil monophosphate cf ₃ with 5-Fluorouracil acetyl cf ₃ 0 4- (N &apos; -iacetyl) cytosine acetyl cf ₃ with 4- (N, N-diacetyl) cytosine acetyl 2-bromo-vinyl 0 4- (N 1 -L-acetyl) cytosine acetyl 2-bromo-vinyl with 4- (N, N-diacetyl) cytosme

Nucleosides of formula XVIII can also be prepared using the appropriate sugars and pyrimidine or purine bases.

Base

R ⁹ R ⁷

R ¹ R ⁵ R ^j X Base R ⁸ Ø ⁵ “ H ch ₃ OH 0 2,4-O-Diacetyluracil H Me H ch ₃ OH 0 Hypoxanthine H Me H ch ₃ OH 0 2,4-O-Diacetylthymine H Me

• · · · · · · · · · · · · · · ·

R ¹ R ⁶ R ¹ X Base R ⁸ R ^y H CH ₃ OH 0 Thymine H Me H ch ₃ OH 0 Cytosine H Me H ch ₃ OH 0 4- (N-mono-acetyl) cytosine H Me H ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Me H ch ₃ OH 0 Uráčil H Me H ch ₃ OH 0 5-Fluorouracil H Me H ch ₃ OH with 2,4-O-Diacetyluracil H Me H ch ₃ OH with Hypoxanthine H Me H ch ₃ OH with 2,4-O-Diacetylthymine H Me H ch ₃ OH with Thymine H Me H ch ₃ OH with Cytosine H Me H ch ₃ OH with 4- (N-mono-acetyl) cytosme H Me H ch ₃ OH with 4- (N, N-diacetyl) cytosine H Me H ch ₃ OH with Uráčil H Me H ch ₃ OH with 5-Fluorouracil H Me monophosphate ch ₃ OH 0 2,4-O-Diacetyluracil H Me monophosphate ch ₃ OH 0 Hypoxanthine H Me monophosphate ch ₃ OH 0 2,4-O-Diacetylthymine H Me monophosphate ch ₃ OH 0 Thymine H Me monophosphate ch ₃ OH 0 Cytosine H Me monophosphate ch ₃ OH 0 4- (N-mono-acetyl) cytosine H Me monophosphate ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Me monophosphate ch ₃ OH 0 Uráčil H Me monophosphate ch ₃ OH 0 5-Fluorouracil H Me monophosphate ch ₃ OH with 2,4-O-Diacetyluracil H Me monophosphate ch ₃ OH with Hypoxanthine H Me monophosphate ch ₃ OH with 2,4-O-Diacetylthymine H Me monophosphate ch ₃ OH with Thymine H Me monophosphate ch ₃ OH with Cytosine H Me monophosphate ch ₃ OH with 4- (N-mono-acetyl) cytosine H Me monophosphate ch ₃ OH with 4- (N _r N- acetyl) cytosine H Me

R ¹ R ⁶ R ⁷ X Base R ⁸ R * monophosphate ch ₃ OH with Uráčil H Me monophosphate ch ₃ OH with 5-Fluorouracil H Me diphosphate ch ₃ OH 0 2,4-O-Diacetyluracil H Me diphosphate ch ₃ OH 0 Hypoxanthine H Me diphosphate ch ₃ OH 0 2,4-O-Diacetylthymine H Me diphosphate ch ₃ OH 0 Thymine H Me diphosphate ch ₃ OH 0 Cytosine H Me diphosphate ch ₃ OH 0 4- (N-mono-acetyl) cytosine H Me diphosphate ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Me diphosphate ch ₃ OH 0 Uráčil H Me diphosphate ch ₃ OH 0 5-Fluorouracil H Me diphosphate ch ₃ OH with 2,4-O-Diacetyluracil H Me diphosphate ch ₃ OH with Hypoxanthine H Me diphosphate ch ₃ OH with 2,4-O-Diacetylthymine H Me diphosphate ch ₃ OH with Thymine H Me diphosphate ch ₃ OH with Cytosine H Me triphosphate ch ₃ OH 0 2,4-O-Diacetyluracil H Me triphosphate ch ₃ OH 0 Hypoxanthine H Me triphosphate ch ₃ OH 0 2,4-O-Diacetylthymine H Me triphosphate ch ₃ OH 0 Thymine H Me triphosphate ch ₃ OH 0 Cytosine H Me triphosphate ch ₃ OH 0 4- (N-mono-acetyl) cytosine H Me triphosphate ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Me triphosphate ch ₃ OH 0 Uráčil H Me triphosphate ch ₃ OH 0 5-Fluorouracil H Me triphosphate ch ₃ OH with 2,4-O-Diacetyluracil H Me triphosphate ch ₃ OH with Hypoxanthine H Me triphosphate ch ₃ OH with 2,4-O-Diacetylthymine H Me triphosphate ch ₃ OH with Thymine H Me triphosphate ch ₃ OH with Cytosine H Me monophosphate cf ₃ OH 0 2,4-O-Diacetyluracil H Me

228 ^VII.

R ¹ R ^ó R ⁷ X Base R ⁸ R ^y monophosphate cf ₃ OH 0 Hypoxanthine H Me monophosphate cf ₃ OH 0 2,4-O-Diacetylthymine H Me monophosphate cf ₃ OH 0 Thymine H Me monophosphate cf ₃ OH 0 Cytosine H Me monophosphate cf ₃ OH 0 4- (N-mono-acetyl) cytosine H Me monophosphate cf ₃ OH 0 4- (N, N-diacetyl) cytosine H Me monophosphate cf ₃ OH 0 Uráčil H Me monophosphate cf ₃ OH 0 5-Fluorouracil H Me monophosphate cf ₃ OH with 2,4-O-Diacetyuracil H Me monophosphate cf ₃ OH with Hypoxanthine H Me monophosphate cf ₃ OH with 2,4-O-Diacetylthymine H Me monophosphate cf ₃ OH with Thymine H Me monophosphate cf ₃ OH with Cytosine H Me monophosphate cf ₃ OH with 4- (N-mono-acetyl) cytosine H Me monophosphate cf ₃ OH with 4- (N + 1-diacetyl) cytosme H Me monophosphate cf ₃ OH with Uráčil H Me monophosphate cf ₃ OH with 5-Fluorouracil H Me acetyl ch ₃ OH 0 4- (N, N-diacetyl) cytosine H Br acetyl ch ₃ OH with 4- (N, N-diacetyl) cytosine H Br

VII. Efficacy against hepatitis C

The compounds are effective against hepatitis C by inhibiting HCV polymerase, inhibiting other enzymes required for the replication cycle, or otherwise.

A number of experiments have been conducted to determine this potency. A general procedure for determining the reproduction of HCV in culture is given in US 5738985 (Miles et al.). In vitro assays have been described by Ferrai et al., Jnl. of Vir., 73, 1649-1654, 1999, Ishii et al., Hepatology, 29,

1227-1235, Lohmann et al., Jnl. of Bio. Chem., 274, 10807-10815, 1999, and Yamashita et al., Jnl. of Bio. Chem., 273, 15479-15486 (1998).

In WO 97/12033 of September 27, 1996 (Emory University, inventors C. Hagedorn and A. Reinoldus with priority), USSN 60/004383 of September 1995, describes an assay for HCV polymerase that can be used to evaluate compounds of the invention. Another assay for HCV polymerase has been described by Bartholomeusz et al., Hepatitis C virus (HCV) RNA polymerase assay using cloned HCV nonstructural proteins, Antiviral Therapy 1996: 1 (Supp 4), 18-24.

Serial assays for reducing kinase activity by various agents are described in US 6030785 (Katze et al), US 6010848 (Devecchio et al) and US 5759795 (Jibin et al). Serial protease inhibition assays are disclosed in US 5861267 (Su et al.), US 5739002 (De Francesco et al.) And US 5597691 (Houghton et al.).

Example 4. Phosphorylation assay

To determine the metabolism of the compounds in the cells, HepG2 cells were taken from the American Type Culture Collection (Rickville, MD) and grown in 225 cm ² flasks in a minimal baseline supplemented with non-essential amino acids and 1% penicillin. and streptomycin. The medium was changed every three days and cells were distributed once a week. The adherent single cell layer was then detached from the support by treatment with 30 ml of trypsin / EDTA for 10 minutes, the cells were washed three times with nutrient medium, and then these HepG2 cells were seeded in

• · • ·

230 amounts of 2.5 x 10 ⁶ cells per well in six-well plates and an amount of 10 pmol [ ³ H] -labelled drug (500 dpm / pmol) was added to the wells for a specified period of time. The cells were maintained at 37 ° C in an atmosphere of 5% carbon dioxide. After a specified period of time, the cells were washed three times with ice-cold physiological saline with phosphate buffered saline, PBS. The active substance inside the cells and its possible metabolites were extracted by incubating the cell pellet overnight at -20 ° C with 60% methanol, then extracting the cells with 20 μΐ of cold ethanol for one hour in an ice bath. The extracts were combined, dried under a gentle stream of filtered air, and stored at -20 ° C until analyzed by HPLC. Preliminary results of this analysis are shown in Table 1 below.

Table 1.

(pmol / million cells) Time (h) pD-2'-CH ₃ - β-ϋ-2'-CH ₃ - pD-2'-CH ₃ - pD-2'-CH ₃ - riboA-TP riboU-TP riboC-TP riboG-TP 2 33.1 0.40 2.24 ND 4 67.7 1,21 3.99 ND 8 147 1.57 9.76 2.85 24 427 6.39 34.9 0.91 30 456 7.18 36.2 3.22 48 288 9.42 56.4 6.26

Example 5. Bioavailability in Cynomolgus monkeys

A week before the start of the tests, monkeys were implanted with a chronic venous catheter and subcutaneous entry into a VAP vein to facilitate blood collection, monkeys were physically examined, including

231 haematological tests and blood serum analysis and their weight was also recorded. The experimental group contained 6 monkeys. Monkeys were given 250 pCi ³ H at each dose of the active ingredient in the form of β-Ώ-2'-CH ₃ -riboG at a dose of 10 mg / kg at a concentration of 5 mg / ml intravenously for three monkeys, IV or oral gavage. in three monkeys, PO. Each dose was weighed prior to administration to know the exact amount of composition administered. Urine samples were then taken at appropriate intervals, approximately 18 to 0 hours prior to drug administration, 0 to 4, 4 to 8, and 8 to 12 hours after administration, and processed. In addition, blood samples were taken prior to drug administration and 0.25, 0.5, 1, 2,

3, 6, 8, 12 and 24 hours after administration of the active ingredient via an established venous catheter and VAP from peripheral blood when blood could not be collected by the catheter. Blood and urine samples were analyzed for the maximum concentration of active substance Cmax / time to reach that maximum concentration Tmax / area under the AUC curve, half-life T _1/2 , CL clearance and V _DC distribution as well as bioavailability F, these values are shown in Tables 2 and 3 and shown graphically in Figures 2 and 3.

Table 2. Oral bioavailability in monkeys

Dose (mg) AUC (ng / ml.h) Nora AUC (ng / ml.h / mg) Avg. Norm AUC (ng / ml.h / mg) F (%) IV monkey 1 46, 44 13614 293.2 IV monkey 2 24.53 6581 268.3 IV monkey 3 20.72 6079 293.4 284.9 PO monkey 1 29, 04 758 26.1 PO monkey 2 30, 93 898 29.0 PO monkey 3 30.04 1842 61.3 38.8 13, 6

232

Table 3. Pharmacokinetics of β-D-2'-CH3-riboG in Cynomolgus monkeys

Method of administration IV AFTER Dose (mg / kg) 10 10 Cmax (ng / ml) 6945.6 ± 1886.0 217.7 ± 132.1 Tmax (h) 0.25 ± 0.00 2.00 ± 1.00 AUC (ng / ml.h) 8758.0 ± 4212.9 1166.0 ± 589.6 Ti / 2 (h) 7.9 ± 5.4 10.3 ± 4.1 CL (1 / h / kg) 1.28 ± 0.48 V _DC (1 / kg) 2.09 ± 0.54 F (%) 13.8

Example 6. Determination of toxicity on bone marrow cells

Human bone marrow cells were collected from normal healthy volunteers and the mononuclear fraction was separated by centrifugation using a Ficoll-Hypaque gradient as described by Sommadossi JP, Carlisle R., Toxicity of 3'-azido-3'-deoxythymidine and 9- (1,3 dihydroxy-2-propoxymethyl) guanine for normal human hematopoietic progenitor cells in vitro, Antimicrobial Agents and Chemotherapy 1987, 31: 452-454, and Sommadossi, JP, Schinazi, RF, Chu CK, Xie MY, Comparison of cytotoxicity of the ( -) and (+) - enantiomer of 2 ', 3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells, Biochemical Pharmacology 1992, 44: 1921-1925. Cell culture assays for CFUGM and BFU-E were performed using bilayer soft agar or methylcellulose. The active ingredients were diluted with nutrient medium and the solution was filtered. After a period of 14 to 18 days at 37 ° C in a humidified atmosphere of 5% carbon dioxide, colonies with more than 50 cells in inverse were counted

233 microscope. The results are shown in Table 4 as percent inhibition of colony formation in the presence of drug compared to control cultures to which only solvent was added.

Table 4. Bone Marrow Cell Toxicity

IC ₅₀ in μΜ Active substance CFU-GM BFU-E ribavirin ~ 5 -1 β-O-2'-CH ₃ -riboA > 100 > 100 β-O-2'-CH ₃ -riboU > 100 > 100 β-ϋ-2'-CH ₃ -riboC > 10 > 10 β-ϋ-2'-CH ₃ -riboG > 10 > 100

Example 7. Determination of toxicity for mitochondria

HepG2 cells were grown on 12-well plates as described above and then exposed to various concentrations of drug as described by Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer, VM. Difference effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells, Antimicrob Agents Chemother 2000, 44: 496-503. After 4 days of drug treatment, the concentration of lactic acid in the nutrient medium was measured using a lactic acid assay kit (Boehringer). The lactic acid concentration was adjusted with respect to the number of cells determined by the haemocytometer. Preliminary results of this test are given in Table 5 below.

• * 234 • · ·

Table 5. Toxicity to mitochondria, acid determination

L-milk

Concentration (μΜ) Lactate (mg / 10 ^s cells) % control Control 2.18 FIAU 10 3.73 170, 4 β-Ό-2'-CH ₃ -riboC 1 2.52 115, 3 10 2.36 107.9 50 2.26 103.4 100 ALIGN! 2.21 101.2

FIAU PD-2'-CH ₃ -riboC

The invention has been described in connection with some preferred embodiments. It will be understood that various modifications may be made within the scope of the invention.

Represented by:

Όι /

235

PATENT CLAIMS

Claims (14)

PATENT CLAIMS A compound of formula I wherein: R @ 1, R @ ² and R @ ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, lipid arrays including phospholipid, amino acid residue, carbohydrate, peptide, cholesterol or may be another pharmaceutically acceptable leaving group after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ^x and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, 236 CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ and R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof. 2. Derivatives of formula II γ where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group. after which cleaved in vivo ·· a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof. 3. A compound of formula (III): EMI3.0 wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents; 238 as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group that cleaves in vivo to give a compound wherein R ¹ , R ² or R ³ independently means a hydrogen atom or a phosphate residue Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ^{5 are} independently hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts or prodrugs thereof. 4. A compound of formula (IV): EMI3.0 wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di-triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, A sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or it may be another pharmaceutically acceptable leaving group which, when cleaved in vivo, yields a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof. 5. Derivatives of formula V (V) 240 where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbyrek phosphate Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof. 241 where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts or precursors thereof. Base 242 7. Derivatives of formulas VII, VIII and IX OR ² Base R ⁶ (VIII) (IX) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) 0 (alkyl), • »·» ♦ T • t t t t t t t t t 243 243 243 243 243 243 243 243 243 243 -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo , fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof. 8. Derivatives of formulas X, XI and XII OR ² OR ³ (X) (XI) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, cleavage in vivo yields a compound wherein R ¹ , R ² or R ³ independently represent an atom. hydrogen or phosphate residue, ^R is hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R 'is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chloro, bromo or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof. 9. Derivatives of formulas XIII, XIV and XV R ^[ O Base OR ² OR ³ (XIV) (XV) where is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof. 10. Derivatives of formula XVI R ^l O Base (XVI): 24 6 where base is a purine or pyrimidine base, so as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, ^R is hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ < • 24.7 R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof. 11. Derivatives of formula XVII R ^l 0 R ^{7 with} R ⁷ (XVII) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo the compound in which R ¹ • • · · · ·. * 248 or R ² independently represent hydrogen or a phosphate, R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ or their pharmaceutically acceptable salts or prodrugs. R ^l 0 ' 12. Derivatives of formula XVIII Base ^R X ** R ⁹ R * $ _v 249 wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chloro, bromo or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and 25 25, O X is O, S, SO ₂ or CH _2, or a pharmaceutically acceptable salt or precursor thereof. A derivative of the formula or a pharmaceutically acceptable salt thereof. A derivative of the formula or a pharmaceutically acceptable salt thereof. ICH, OH OH • · · · 251 or 16. a pharmaceutically acceptable salt thereof. Derivative of formula or 17. or 18. a pharmaceutically acceptable salt thereof. Derivative formula A derivative of the formula or a pharmaceutically acceptable salt thereof. .252 * A derivative of the formula or a pharmaceutically acceptable salt thereof. 20. Derivative of the formula OH OH or a pharmaceutically acceptable salt thereof. A derivative of the formula or a pharmaceutically acceptable salt thereof. 253 * or a pharmaceutically acceptable salt thereof. A derivative of the formula or a pharmaceutically acceptable salt thereof. A derivative of the formula or a pharmaceutically acceptable salt thereof. . * 254 Derivatives according to any one of claims 1 to 24 in unit dosage form. Derivatives according to claim 25 in a dosage form containing 10 to 1500 mg of the derivative. Derivatives according to claim 25 or 26 in a dosage form which is a tablet or a capsule. 28. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises, as an active ingredient, an effective amount of a compound of formula (I): What where R ¹ , R ² and R ^J independently represent hydrogen, a phosphate residue (including a mon-, di- or triphosphase and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including lower alkyl groups, a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁴ independently represent hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 29. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus infection comprising an effective amount of a compound of formula II as an active ingredient. 256 where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable leaving group. after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of the general formula III; R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 31. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula IV as an active ingredient. R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents a hydrogen, bromine, chlorine, fluorine, iodine or OR ⁴ , NR ⁴ R ⁵ or SR ⁴ atom, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 32. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises as an active ingredient an effective amount of a derivative of formula (V): R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, such as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or a moiety. o another pharmaceutically acceptable cleavable group which, after cleavage in vivo, yields a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ³ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of the general formula VI R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di- or triphosphate and • · ·· · ···· < A phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups, such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol, or other pharmaceutically acceptable cleavable group, which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbycek phosphate Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R 5 ^are independently hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 34. A pharmaceutical composition of hepatitis C virus infection comprising, as an active ingredient of a compound of formula (VII), for the treatment or treatment of: IX Base OR ¹ OR ³ (VH) prophylaxis with amounts Base R ^s (K) fr · fr « 262 wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 35. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of the general formula X, XI and XII wherein the base is a purine or pyrimidine base as defined above. R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , <RTIgt; .264, </RTI><RTIgt; a * · · R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 36. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formulas XIII, XIV and XV as an active ingredient. 1, -i OR-OR C ™) wherein the base is a purine or pyrimidine base as defined, R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl or «· Arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbycek phosphate R 0 represents hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 37. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of formula (XVI) as an active ingredient. RO Base X R ‘(XVI) wherein the base is a purine or pyrimidine base as defined, 26.4 .. :: · Hydrogen atom, phosphate residue R ¹ and R ² independently represent (including mono-, di- or triphosphate and stabilized phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound, wherein R ¹ and R ² independently represent hydrogen or a phosphate, ^R is hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -0 ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ^{8 10} optionally forms a bond and X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 38. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of formula (XVII) as an active ingredient. R? 0 Base R ⁹ R ⁷ (XVII) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed in which R ¹ : 268 or R ² independently represents a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -0 (lower acyl), -0 (alkyl), -0 (lower alkyl), -0 (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ is hydrogen, alkyl including a lower alkyl group, chlorine, bromine or iodine, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X is O, S, SO ₂ or CH ₂ , as well as and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of formula (XVIII). Base in R (xvm) 2 6 9 Wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent. 40. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula: Or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 41. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. • · · · · · · · · · · · · · · · · 42. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 43. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. • · 44. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 45. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 46. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus infection comprising an effective amount of a derivative of the formula 273, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 47. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula: OH OH or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 48. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of formula: 274, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 49. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 50. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula: Or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 51. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 52. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises as an active ingredient an effective amount of a compound of formula I: (I) where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 53. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a compound of formula II as active ingredient. • ffff. * 2 · 77 ffff »« ff o · ♦ ff ff V • ff » R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ and 2.7-8. R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 54. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises as an active ingredient an effective amount of a derivative of formula III wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable salt. • · acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 55. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises as an active ingredient an effective amount of a derivative of the formula (IV): R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di-, or triphosphate, and "· · · * precursor stabilized phosphate), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other a pharmaceutically acceptable leaving group which, after cleavage in vivo, yields a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. Pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of the general formula V wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or may be another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group; 2g £. As well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 57. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the general formula VI as an active ingredient. Y R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, 2β · 3 X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 58. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of formula (VII), (VIII) and (IX) as an active ingredient. Base R ^l 0 OR OR (vu) RO. Base (K) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents; 28 * 4. : as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group that cleaves in vivo to form a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 59. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of formula X, XI and XII (X) (XI) as an active ingredient; ; . z-oj. . . .... Where the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl- and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group. after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) 2 / -N (acyl) _2, and X represents 0, S, S0 ₂ or CH _2, 236.: as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 60. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of formula (XIII), (XIV) and (XV) as an active ingredient. Base OR ^: OR ³ TO (XV) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after cleavage in A compound in which R ¹ , R ² or R ^{3 is} independently hydrogen or phosphate is formed in vivo to form a compound. R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH _{2 ',} and pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 61. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, characterized in that it comprises as an active ingredient an effective amount of a derivative of formula XVI (XVI) wherein the base is a purine or pyrimidine base as defined above. R ¹ and R ² independently represent hydrogen, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as 280 methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable cleavable group; which cleaved in vivo by a compound in which R ¹ or R ² independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) 2 / -N (acyl) ₂ and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 2 £ 9. • 9 9 • 9 62. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of formula XVII (XVH) wherein the base is a purine or pyrimidine base as defined above, as an active ingredient; R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ^e is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, 2J0. alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N ( acyl) ₂ a R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as and pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 63. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, which comprises an effective amount of a derivative of formula XVIII (xvm) * 29 * as an active ingredient. wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and 2? 2. : X is O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 64. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 65. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the formula I i ch ₃ OH OH «·· 29.5 • * As well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 66. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 67. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula: HIM. 294 as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 68. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 69. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a compound of formula (I) ^CH3OH OH 295, as well as pharmaceutically acceptable salts thereof, in combination with one or more other antiviral agents. 70. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 71. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus infection comprising an effective amount of a derivative of the formula OH OH 296 as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 72. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula: OH OH as well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 73. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis C virus infection comprising an effective amount of a derivative of the formula OH OH As well as pharmaceutically acceptable salts thereof in combination with one or more other antiviral agents. 74. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection, comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 75. A pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection comprising an effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof in combination with one or more other antiviral agents. 298 A pharmaceutical composition according to any one of claims 28 to 75, characterized in that it is in unit dosage form. 77. A pharmaceutical composition according to claim 76 containing 10 to 1500 mg of active ingredient per unit dose. 78. A pharmaceutical composition according to claim 76 or 77, in the form of a tablet or capsule. 79. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a compound of formula I O) where R ^1, R ² and R ³ independently represent hydrogen atom, a phosphate (včerně mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl groups or arylalkylsulfonylových , such as methanesulfonyl and 299 benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group after cleavage in in vivo, a compound is formed wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof. 80. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula II. 30 «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof. 81. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula III. 301 * R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof. 302 82. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula IV (IV) wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ and R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof. 83. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an anti-virally effective amount of a compound of formula V (V) wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable 304? an acceptable leaving group to cleave in vivo to give a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof. 84. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula VI wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups , such as methanesulfonyl and 305:: Benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable leaving group; which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbycek phosphate Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent hydrogen, acyl including lower acyl or alkyl including methyl, ethyl, propyl and cyclopropyl, as well as pharmaceutically acceptable salts thereof. 85. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula VII, VIII and IX. Where the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ ? -N (acyl) _2, and X represents 0, S, S0 ₂ or CH _2, and pharmaceutically acceptable salts thereof. 86. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula X, XI and XII wherein the base is a purine or pyrimidine base as defined above. R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, ^R is hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , 00 308 · * • 0 0 0 » 0 0 » R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH 2, -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof. 87. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula (XIII), (XIV) and (XV) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and »* 9 · 309 ·. Benzyl, wherein the phenyl group is optionally substituted with one or more benzyl groups; or a plurality of substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ , R 1 ² or R ³ independently represent a hydrogen atom or a phosphate residue, R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof. 88. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula XVI wherein the base is a purine or pyrimidine base as defined, R @ ¹ and R @ ² independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and stabilized); • · * · · O 1 · · · · · · · (Phosphate precursor), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein: the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group that cleaves in vivo to form a compound, wherein R ¹ and R ² independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a X represents 0, S, S0 ₂ or CH _2, and pharmaceutically acceptable salts thereof. 89. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula XVII (XVH) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower) 312 alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) 2, -N (acyl) _2, and R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as and pharmaceutically acceptable salts thereof. 90. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula (XVIII) _{R ( Q)} R ^{9 7 7} (xvm) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, a sulfonate ester Including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or o another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ or R ^{2 is} independently hydrogen or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as and pharmaceutically acceptable salts thereof. 91. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula: ## STR2 ## :: or a pharmaceutically acceptable salt thereof. 92. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 93. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula HIM. • · · · · · · · 31! or a pharmaceutically acceptable salt thereof. 94. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 95. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. .31 $ • * · · · · · · · · 96. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 97. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 98. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula. or a pharmaceutically acceptable salt thereof. 99. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 100. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 101. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 102. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula or a pharmaceutically acceptable salt thereof. 103. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula I CD kde R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups , such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or may be another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ and R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 104. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a compound of formula II Where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, such as: As described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or may be another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 105. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula III. 332 ··. : where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 106. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the general formula IV wherein * 323 * R‘0 OR OR '(IV) R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di- and triphosphate sky precursor stabilized phosphate), acyl including lower acyl, alkyl including lower alkyl, sulfonate ester including alkyl groups or arylalkylsulfonylových such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol, or may be another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbycek phosphate Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group; 324 as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents effect. 107. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula V wherein: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 108. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula VI R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups , such as methanesulfonyl and benzyl, wherein the phenyl group is optionally 326 substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ^1, R ² or R ³ independently represent hydrogen or zbyrek phosphate Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 109. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula VII, VIII and IX (VE). Base (IX) R ^s Wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH ₂ , as well as a pharmaceutically acceptable salt thereof, in combination or alternatively with one or more other antiviral agents. 110. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of Formula X, XI and XII. 328 (XI) (XH) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine, or • 32 9: iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. ¹¹¹ 111. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula XIII, XIV and XV. OR ² OR ³ (xm) wherein the base is a purine or pyrimidine base as defined, R ^1, R ² and R ³ independently represent a hydrogen atom, phosphate (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including lower ·· »« 3 * 30 acyl groups, alkyl including lower alkyl, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, lipid residue including phospholipid, amino acid residue, carbohydrate, peptides, cholesterol, or another pharmaceutically acceptable leaving group that cleaves in vivo to give a compound wherein R ¹ , R ^2, or R ^{3 is} independently hydrogen or phosphate, R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CK ₂ , as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 112. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a compound of formula XVI R ^l O. Base R · R ^and (XVI) R ⁹ R ⁷ «· 0 · wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ·· .333 * A * t · t · t · ttt » R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a X is O, S, SO ₂ or CH ₂ , as well as pharmaceutically acceptable salts thereof, in combination or alternatively with one or more other antiviral agents. 113. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an anti-viral effective amount of a derivative of formula XVII (XVII) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, 4 4 »* · * · • ········· The carbohydrate, peptides, cholesterol or other pharmaceutically acceptable leaving group may be formed to cleave in vivo to form a compound wherein R ¹ or R ^{2 is} independently hydrogen or phosphate, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ is hydrogen, alkyl including a lower alkyl group, chlorine, bromine or iodine, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X is O, S, SO ₂ or CH ₂ , as well as and pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. 114. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula (XVIII) **. · Jj «···· · 9 9 » 999 9 999 9999 ♦ · 9999 (xvm) where the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (0) 0 (lower alkyl), -O ( acyl), -0 (lower acyl), -0 (alkyl), -0 (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) -NH (acyl) -N (lower alkyl) ₂ -N (acyl) ₂ 335 R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chloro, bromo or iodo, ΝΟ ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as and pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. 115. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 116. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula As well as pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. 117. A method of treating or prophylaxis of hepatitis C virus infection comprising administering an antiviral effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 118. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula. as well as pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. 119. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral active compound of the formula and pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. effect. 120. A method for the treatment or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula and a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 121. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula and a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 122. A method for treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula 339 as well as pharmaceutically acceptable salts thereof, in combination or in combination with one or more other antiviral agents. 123. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula as well as a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 124. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula and a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 125. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of the formula and a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 126. A method of treating or prophylaxis of hepatitis C virus infection, comprising administering an antiviral effective amount of a derivative of formula (I) as well as a pharmaceutically acceptable salt thereof, in combination or in combination with one or more other antiviral agents. 127. The method of any one of claims 89 to 126, wherein the active ingredient is administered in a unit dose dosage form. 128. The method of claim 127, wherein the dosage form comprises 10 to 1500 mg of active ingredient per unit dose. 129. The method of claim 127 or 128, wherein the dosage form is a tablet or capsule. 130. Use of a derivative of the general formula I (I) 342 where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, cleavage in vivo yields a compound in which R, R or R independently represents a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 131. Use of a derivative of the general formula II. * 34,3 • · (Π) where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 132. Use of a derivative of general formula III (ET) wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched, or cyclic alkyl, CO-alkyl, C--C CO-C CO-C,-C,-C,-C,-C,-C,-C,-C, alkyl; · · · CO-aryl, CO-alkoxyalkyl, chlorine, bromine, fluorine, iodine, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ and R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 133. Use of a derivative of the general formula IV R ¹ , R ² and R ³ independently represent a hydrogen aroma, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, 3-4 δ · · · · · · Υ represents a hydrogen, bromine, chlorine, fluorine, iodine or OR ⁴ , NR ⁴ R ⁵ or SR ⁴ atom, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 134. Use of a derivative of the general Formula V wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including, but is not limited to, a moiety including a lipid moiety. A phospholipid, amino acid residue, carbohydrate, peptide, cholesterol or other pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 135. Use of a derivative of the general formula VI R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and 348: Benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol, or it may be another pharmaceutically acceptable leaving group which, when cleaved in vivo, yields a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 136. Use of a derivative of formula (VII), (VIII) and (IX) wherein the base is a purine or pyrimidine base, as defined: R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or zbyzek phosphate R 0 represents hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-3r-ethyl, -C (O) O (alkyl), -C (O) O (lower) alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo, fluoro or iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 137. Use of a derivative of formula X, XI and XII OR ² OR ³ (X) (XI) where 350 is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) 2, -N (acyl) ₂ , R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO _2. , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH ₂ . 351. As well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 138 Use of a derivative of the formulas XIII, XIV and XV Base OR ² OR ³ OR ² (XIV) (XV) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower • 3-2 alkyl), - O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) 2, -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 139. Use of a derivative of the general formula XVI (XVI) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), an acyl of a lower lower acyl group, an alkyl including a lower alkyl group, a sulfonate ester including an alkyl- or arylalkylsulfonyl group such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group after cleavage In vivo, a compound is formed wherein R ¹ or R independently is hydrogen or phosphate,. 3; 53 R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) 2, -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ³ and R ⁹ or R ⁸ and R ¹⁰ optionally form pi -binding a X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C infection. 140. Use of a derivative of formula XVII Base (xvn) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and * 7 Q 2 R and R independently represent hydrogen, OR, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , 3 ^ 5. R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as of pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 141 Use of derivative R ^! Ct of formula XVIII Base R ⁹ R ⁷ (XVIII) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, ^R is hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl ·), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl ), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ³ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as of pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 142. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 143. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 145. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 358 146. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 147. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 148. Use of a derivative of the formula OH OH And pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 149. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 151. Use of a derivative of the formula OH OH · · «· 360. : as well as pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 152. Use of a compound of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 153. Use of a compound of the formula and pharmaceutically acceptable salts thereof for the treatment or prophylaxis of hepatitis C virus infection. 154. Use of a derivative of the formula I © 36Γ where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. «» » 3 52 155. Use of a derivative of the Formula II (Π) wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylakylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen phosphate sky rest, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a * w * 9 9 9 · 3 £ 3 » 9 · 9 9 9 9 R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 156. Use of a derivative of the general formula III (ΙΠ) where R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or another pharmaceutically acceptable leaving group, cleavage in vivo yields a compound wherein R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate moiety; : fcfcfcfcfcfcfcfc Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 157. Use of a derivative of the general formula IV R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including 3S5 phospholipid, amino acid residue, carbohydrate, peptide, cholesterol or other pharmaceutically acceptable cleavable group which, when cleaved in vivo, yields a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 158. Use of a derivative of the general Formula V wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including lower; 366 acyl groups, alkyl including lower alkyl, sulfonate ester including alkyl or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more by the number of substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or may be another pharmaceutically acceptable cleavable group to cleave in vivo to form a compound wherein R ¹ , R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 159. Use of a derivative of the general Formula VI (VI) wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or other pharmaceutically acceptable cleavable group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, Y represents hydrogen, bromine, chlorine, fluorine, iodine, or OR ^4, NR ⁴ R ⁵ or SR ^4, X ¹ and X ² are independently selected from hydrogen, straight, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR ⁴ , NR ⁴ NR ⁵ or SR ⁵ a R ⁴ and R ⁵ independently represent a hydrogen atom, an acyl group including a lower acyl group or an alkyl group including a methyl, ethyl, propyl and cyclopropyl group, as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 160. Use of a derivative of the general formulas VII, VIII and IX 3 * 68. (IX) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁶ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-3r-ethyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), CF ₃ , chloro, bromo , fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X is O, S, SO ₂ or CH ₂ Or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis of hepatitis C virus infection. 161. Use of a derivative of the general formula R ^j 0 wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group, after which cleaved in vivo by a compound in which R ^1, R ² or R ³ independently represent hydrogen or a phosphate, R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower * 0 · 37 alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO2, _NH2, -NH (lower alkyl), -NH (acyl), -N (lower alkyl) _2, -N (acyl) ₂ , R ⁷ is hydrogen, OR ³ , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection. 162. Use of a derivative of the formulas XIII, XIV and XV OR ² OR ³ (xm) (XV) wherein the base is a purine or pyrimidine base as defined, R ¹ , R ² and R ³ independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, 371. a sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, a peptide, cholesterol or be another pharmaceutically acceptable cleavable group to cleave in vivo to give a compound in which R ¹ , R ² or R ³ independently represent a hydrogen atom or a phosphate residue, R ⁵ is hydrogen, hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 163. Use of a derivative of the general Formula XVI wherein the base is a purine or pyrimidine base as defined herein. R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as is methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for the aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or may be another pharmaceutically acceptable leaving group after cleavage in vivo results in a compound in which R ¹ or R ² independently represents a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -0 (lower acyl), -0 (alkyl), -0 (lower alkyl), -0 (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ to R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O (lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O ( alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁸ and R ¹⁰ independently represent hydrogen, alkyl including lower alkyl, chlorine, bromine or iodine, or R ⁷ and R ⁹ , R ⁷ and R ¹⁰ , R ⁸ and R ^{8 9} or R ⁸ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C infection. 164. Use of a derivative of the general Formula XVII (XVH) wherein the base is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol, or another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is obtained in which R @ ¹ or R @ ² independently represent a hydrogen atom or a phosphate radical, 3 7 4 · · · · · · · * · · · · · · · · R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) _2, and R ⁷ and R ⁹ independently represent hydrogen, OR ² , hydroxy, alkyl including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (O) O (alkyl), -C (O) O ( lower alkyl), -O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , - NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ¹⁰ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁷ and R ¹⁰ optionally form a bond and X represents O, S, SO ₂ or CH ₂ as well as of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 165. Use of a derivative of the general formula XVIII (xvm) wherein f is a purine or pyrimidine base as defined, R ¹ and R ² independently represent a hydrogen atom, a phosphate residue (including a mono-, di- or triphosphate and a stabilized phosphate precursor), acyl including a lower acyl group, alkyl including a lower alkyl group, sulfonate ester including alkyl- or arylalkylsulfonyl groups such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described for an aryl group, a lipid residue including a phospholipid, an amino acid residue, a carbohydrate, peptides, cholesterol or may be another pharmaceutically acceptable cleavable group after cleavage in vivo, a compound is formed wherein R ¹ or R ² independently represent a hydrogen atom or a phosphate residue, R ⁶ represents hydrogen, hydroxyl, alkyl, including lower alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, -C (0) 0 (alkyl), -C (O) O (lower alkyl), -O ( acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), chlorine, bromine, fluorine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl) , -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ , R ⁷ and R ⁹ independently represent hydrogen, OR ² , alkyl including lower alkyl, alkenyl, alkynyl, Br-vinyl, -O (alkenyl), chlorine, bromine or iodine, NO ₂ , NH ₂ , -NH (lower alkyl), di (lower alkylamino), R ⁸ represents a hydrogen atom, an alkyl including a lower alkyl group, a chlorine, bromine or iodine atom, or R ⁷ and R ⁹ or R ⁸ and R ⁹ optionally form a bond; ⁶ ' 9 9 9 » 94 94 * »• in» i »4 4« I »· *» · X represents O, S, SO ₂ or CH ₂ as well as pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis C virus infection. 166. Use of a derivative of the formula as a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 167. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 168. Use of the derivative of the formula <r · · * 94 4 4 * · 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** And pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C infection. 169. The use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 170. Use of a derivative of the formula 1 | CHj OH OH 378 as well as pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 171. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 172. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 173. Use of a derivative of the formula • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · · ···· 379 OH OH and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C infection. 174. The use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 175. Use of a derivative of the formula OH OH · · · 380, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C infection. 176. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 177. Use of a derivative of the formula and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of hepatitis C virus infection. 178. The use of a derivative according to any one of claims 130 to 177 for the manufacture of a pharmaceutical composition in a dosage form. 381 Use according to claim 178, wherein the dosage form contains from 10 to 1500 mg of active ingredient per unit dose 180. The use of claim 178 or 179, wherein the dosage form is a tablet or capsule. Represented by: